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Simple Summary: The ongoing research of extracellular vehicles (EVs including exosomes, ectosomes, and apoptotic bodies) is gaining momentum to understand these vesicles' biology and clinical applications in cancer disease. The current limitations of using standard tumor biomarkers warrant the development of novel and reliable biomarkers to meet clinical needs. Exosomes are used as tumor biomarkers, for targeted therapy, for vaccine development, and as a vehicle for drug delivery. Here, we summarized the current approaches for different methods of EV isolation and EV cargo compositions, such as nucleic acids, proteins, and lipids. The unique cargo composition of exosomes makes it a potential candidate for liquid biopsies in the diagnosis and prognosis of cancer patients. Furthermore, the review highlights the use of machine learning algorithms to analyze complex EV datasets and create more robust models for biomarker discovery. Early cancer detection and accurate monitoring are crucial to ensure increased patient survival. Recent research has focused on developing non-invasive biomarkers to diagnose cancer early and monitor disease progression at low cost and risk. Extracellular vesicles (EVs), nanosized particles secreted into extracellular spaces by most cell types, are gaining immense popularity as novel biomarker candidates for liquid cancer biopsy, as they can transport bioactive cargo to distant sites and facilitate intercellular communications. A literature search was conducted to discuss the current approaches for EV isolation and the advances in using EV-associated proteins, miRNA, mRNA, DNA, and lipids as liquid biopsies. We discussed the advantages and challenges of using these vesicles in clinical applications. Moreover, recent advancements in machine learning as a novel tool for tumor marker discovery are also highlighted. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholesterol and cholesterol derivatives accumulate in prostate cancer cells. Epidemiologic studies about diet and/or treatment with cholesterol-lowering drugs indicate that this metabolite plays a role in cancer progression, but they do not discriminate its possible role in cancer incidence. The goal of this study is so to determine whether cholesterol availability impacts tumor formation itself. Using a drosophila model specifically dedicated to the study of early epithelial tumorigenesis, we find that basal extrusion, a critical step of tumor formation, directly depends on cholesterol availability through dietary intake, and on cholesterol metabolization by the tumor cells. As we find that many genes related to cholesterol homeostasis and metabolism are ill-expressed in primary prostate cancer samples, this work indicates that cholesterol levels and metabolism could play a crucial role in the early phases of prostate cancer as well. Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in the Drosophila melanogaster accessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical cancer is the fourth most prominent cancer in women worldwide. Early cancer detection, timely treatment, and prognostic marker identification are vital to ensure that patients have improved outcomes. Magnetic resonance spectroscopy (MRS) is a powerful tool for detecting metabolites in vivo. This review article covers the role of MRS for cervical cancer for diagnosis, treatment response evaluation, and future applications of this technology. This review article investigates the utilization of MRS in the setting of cervical cancer. A variety of different techniques have been used in this space including single-voxel techniques such as point-resolved spectroscopy (PRESS) and stimulated echo acquisition mode spectroscopy (STEAM). Furthermore, the experimental parameters for these acquisitions including field strength, repetition times (TR), and echo times (TE) vary greatly. This study critically examines eleven MRS studies that focus on cervical cancer. Out of the eleven studies, ten studies utilized PRESS acquisition, while the remaining study used STEAM acquisition. These studies generally showed that the choline signal is altered in cervical cancer (4/11 studies), the lipid signal is generally increased in cervical cancer or the lipid distribution is changed (5/11 studies), and that diffusion-weighted imaging (DWI) can quantitatively detect lower apparent diffusion coefficient (ADC) values in cervical cancer (2/11 studies). Two studies also investigated the role of MRS for monitoring treatment response and demonstrated mixed results regarding choline signal, and one of these studies showed increased lipid signal for non-responders. There are several new MRS technologies that have yet to be implemented for cervical cancer including advanced spectroscopic imaging and artificial intelligence, and those technologies are also discussed in the article. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell–cell communication mechanisms are gathering growing scientific interest, particularly in the context of cancer cells and the tumor microenvironment. Extracellular vesicles are gaining increased interest due to their relevance in tumor molecular characterization, classification, diagnosis, prognosis evaluation, and response to treatment. Many advances have been made in the clinical and therapeutic fields, exploiting increasingly precise biomolecular engineering strategies. This review aims to focus on the role of extracellular vesicles (EVs) as diagnostic and therapeutic tools in lung cancer. Lung cancer represents the leading cause of cancer-related mortality worldwide, with around 1.8 million deaths in 2020. For this reason, there is an enormous interest in finding early diagnostic tools and novel therapeutic approaches, one of which is extracellular vesicles (EVs). EVs are nanoscale membranous particles that can carry proteins, lipids, and nucleic acids (DNA and RNA), mediating various biological processes, especially in cell–cell communication. As such, they represent an interesting biomarker for diagnostic analysis that can be performed easily by liquid biopsy. Moreover, their growing dataset shows promising results as drug delivery cargo. The aim of our work is to summarize the recent advances in and possible implications of EVs for early diagnosis and innovative therapies for lung cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Erastin is a small molecule that was discovered in a screen to selectively kill cancer cells. Mechanistic studies of the cancer cells killed by erastin determined their death to be dependent on iron, increased levels of lipids and oxidative stress. This type of cell death was called "ferroptosis". We hypothesized that even low levels of erastin would lead to changes in signaling pathways in the cell. To test this, we exploited an ex vivo blood–brain barrier transport assay and confirmed our findings in vitro in human tumor cells. We determined that nanomolar levels of erastin could induce specific biological changes in the activity of an important transporter (pump) at the BBB and in tumor cells. We showed that erastin rapidly inhibited the activity of the Multidrug-Resistant Protein (MDR1, P-glycoprotein). Noteworthy, P-glycoprotein is responsible for most of the chemo-resistance in cancer therapies. The blood–brain barrier is composed of both a physical barrier and an enzymatic barrier. Tight junction (TJ) proteins expressed between endothelial cells of brain capillaries provide the physical barrier to paracellular movement of ions and molecules to the brain, while luminal-facing efflux transporters enzymatically restrict the entry of blood-borne molecules from entering the brain. The expression and activity of ATP Binding Cassette transporters or "ABC" transporters in endothelial cells of the BBB and in human tumor cells are dynamically regulated by numerous signaling pathways. P-glycoprotein (P-gp), (ABCB1), is arguably the most studied transporter of the BBB, and in human cell lines. P-glycoprotein transport activity is rapidly inhibited by signaling pathways that call for the rapid production of nitric oxide (NO) from the inducible nitric oxide synthase enzyme, iNOS. This study investigated how nano-molar levels of the selective chemotherapeutic erastin affect the activity or expression of P-glycoprotein transporter in brain capillaries and in human tumor cell lines. We chose erastin because it signals to iNOS for NO production at low concentrations. Furthermore, erastin inhibits the cellular uptake of cystine through the XC− cystine/glutamate antiporter. Since previous reports indicate that NO production from iNOS can rapidly inhibit P-gp activity in tumor cells, we wondered if induction of iNOS by erastin could also rapidly reduce P-glycoprotein transport activity in brain endothelial cells and in human tumor cell lines. We show here that low concentrations of erastin (1 nM) can induce iNOS, inhibit the activity of P-glycoprotein, and reduce the intracellular uptake of cystine via the Xc- cystine/glutamate antiporter. Consistent with reduced P-glycoprotein activity in rat brain capillary endothelial cells, we show that human tumor cell lines exposed to erastin become more sensitive to cytotoxic substrates of P-glycoprotein. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is recognized as the most common cancer within the female population. In this context, cholesterol is recognized as a vital component for the proliferation and survival of cancer cells. These cells primarily acquire cholesterol through the receptor-mediated uptake from external sources, including low-density lipoprotein (LDL), utilizing the endocytosis pathway. Thus, this observational study aimed to test the effectiveness of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in cancer onset. Although PCSK9 correlated with lipid parameters (e.g., cholesterol, LDL) and with 17 β-estradiol, our results do not portend PCSK9 is a prognostic biomarker, at least, in the context of breast neoplastic events. Background and aim: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. Methods: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. Results: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170–252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999–1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = −0.305), maintained even after partial adjustment for BMI and age (r = −0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. Conclusions: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer therapy suffers from a lack of effective targets because, typically, success with blockade of the androgen receptor gives way to drug resistance and lethal disease relapse. Large scale genome sequencing efforts have demonstrated that lethal recurrent disease most often presents with loss of the PTEN and TP53 tumor suppressors. Unfortunately, the systematic testing of PTEN/ PI 3-Kinase pathway-specific inhibitors has shown only limited results in prostate cancer trials. Thus, there are currently no FDA-approved drugs targeting this axis in prostate cancer patients. Here we propose a new target, the FABP5 lipid carrier. FABP5 amplification and surge in expression are strongly correlated to that of the MYC oncogene, a known driver of advanced PTEN-deficient prostate cancer. Here, we present a new pre-clinical platform to assess the efficacy and biology of inhibiting FABP5 with small molecules. Our platform is based on a PTEN-deficient prostate cancer cell type that is insensitive to standard of care therapies. Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in PTEN-deficient PC. [ABSTRACT FROM AUTHOR]

Simple Summary: Statins are crucial for managing lipid disorders by inhibiting HMG-CoA reductase, reducing cholesterol levels, and lowering cardiovascular disease risk. Beyond cholesterol control, they exhibit pleiotropic effects, particularly in cancer. Statins influence key cancer pathways, inhibiting proliferation, angiogenesis, metastasis, and cancer stemness, while inducing oxidative stress, cell cycle arrest, autophagy, and apoptosis. Clinical studies suggest statin use associates with reduced cancer risk, lower-grade tumors at diagnosis, decreased local recurrence, and improved survival. This review aims to summarize the mechanisms underpinning statins' anticancer properties and their clinical implications, highlighting their potential as a valuable tool in cancer prevention and treatment. Statins are an essential medication class in the treatment of lipid diseases because they inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. They reduce cholesterol levels and reduce the risk of cardiovascular disease in both primary and secondary prevention. In addition to their powerful pharmacologic suppression of cholesterol production, statins appear to have pleitropic effects in a wide variety of other diseases by modulating signaling pathways. In recent years, statins have seen a large increase in interest due to their putative anticancer effects. Statins appear to cause upregulation or inhibition in key pathways involved in cancer such as inhibition of proliferation, angiogenesis, and metastasis as well as reducing cancer stemness. Further, statins have been found to induce oxidative stress, cell cycle arrest, autophagy, and apoptosis of cancer cells. Interestingly, clinical studies have shown that statin use is associated with a decreased risk of cancer formation, lower cancer grade at diagnosis, reduction in the risk of local reoccurrence, and increasing survival in patients. Therefore, our objective in the present review is to summarize the findings of the publications on the underlying mechanisms of statins' anticancer effects and their clinical implications. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian tumors mobilize a heterogenous population of myeloid cells. While these cells initially contribute to anti-tumor immunity, as cancer progresses, they switch from immunostimulatory to immunosuppressive. Ovarian cancer is most frequently restricted to the peritoneal cavity, negating the need for systemic delivery of therapeutics. With a goal of targeting and activating myeloid cells in the tumor microenvironment, this study sought to determine which nanoparticle characteristics enhance uptake by myeloid cells in vitro and in vivo using an animal model of ovarian cancer. Lipids coating a mesoporous silica core were optimized for surface charge, formulation, and inclusion of immunogenic monophosphoryl lipid A. Benefits of a mesoporous core include opportunities for loading with additional therapeutics, such as antigens to direct immune responses or other therapeutic payloads that facilitate anti-cancer immune responses. Immunogenic lipid-coated mesoporous silica nanoparticles (ILM) present pathogen-associated molecular patterns (PAMPs) on the nanoparticle surface to engage pathogen-associated receptors on immune cells. The mesoporous core is capable of loading additional immunogens, antigens or drugs. In this study, the impact of lipid composition, surface potential and intercalation of lipophilic monophosphoryl lipid A (MPL-A) in the lipid coat on nanoparticle properties and cellular interactions is presented. Loading and retention of the model antigen ovalbumin into the mesoporous silica core were found to be similar for all nanoparticle formulations, with presentation of ova peptide (SIINFEKL) by major histocompatibility complex (MHC) evaluated to facilitate the selection of an anionic nanoparticle composition. ILM were able to induce lysosomal tubulation and streaming of lysosomes towards the cell surface in dendritic cells, leading to an enhanced surface presentation of MHC. Myeloid cells robustly internalized all ILM formulations; however, non-myeloid cells selectively internalized cationic ILM in vitro in the presence of 20% serum. Interestingly, ILM administration to the peritoneal cavity of mice with disseminated ovarian cancer resulted in selective accumulation of ILM in tumor-associated tissues (>80%), regardless of nanoparticle surface charge or the presence of MPL-A. Immunofluorescence analysis of the omental tumor showed that ILMs, regardless of surface charge, were localized within clusters of CD11b+ myeloid cells 24 h post administration. Selective uptake of ILMs by myeloid cells in vivo indicates that these cells outcompete other cell populations in the ovarian tumor microenvironment, making them a strong target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of hypopharyngeal cancer has been rapidly increasing, but hypopharyngeal cancer has a poorer prognosis compared to other head and neck cancers. This is because the diagnosis of hypopharyngeal cancer is late due to few symptoms in the early stages. Thus, early diagnosis and prevention are very important in the management of hypopharyngeal cancer. Metabolic syndrome, including a combination of obesity, impaired lipid and glucose metabolism, and hypertension, has recently attracted attention as a risk factor for various cancers. In this study, we investigated the association between metabolic syndrome and hypopharyngeal cancer. We confirmed that metabolic syndrome lowered the risk of hypopharyngeal cancer regardless of age, sex, smoking, and alcohol consumption. This inverse association was more prominent in women than in men. This study evaluated the relationship between metabolic syndrome (MS) and the risk of hypopharyngeal cancer. This retrospective cohort study used data from the Korean National Health Insurance Research Database. A total of 4,567,890 participants who underwent a health checkup in 2008 were enrolled. The participants were followed until 2019, and the incidence of hypopharyngeal cancer was analyzed. We evaluated the risk of hypopharyngeal cancer according to the presence of MS, including obesity, dyslipidemia, hypertension, and diabetes, using a multivariate Cox proportional hazards model adjusted for age, sex, alcohol consumption, and smoking. During the follow-up period, 821 were newly diagnosed with hypopharyngeal cancer. MS was inversely associated with the risk of hypopharyngeal cancer (hazard ratio (HR), 0.83 [95% confidence interval (CI), 0.708–0.971]). Large waist circumference and high triglyceride levels among MS elements were both inversely related to the risk of hypopharyngeal cancer (HR: 0.82 [95% CI, 0.711–0.945] and 0.83 [95% CI, 0.703–0.978], respectively). The risk of hypopharyngeal cancer decreased with increasing comorbidity of MS in women (N = 0 vs. N = 1–2 vs. N ≥ 3; HR = 1 vs. HR = 0.511 [95% CI, 0.274–0.952] vs. HR = 0.295 [95% CI, 0.132–0.66]), but not in men. This study may improve our etiological understanding of hypopharyngeal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The disialoganglioside GD2 is produced at high levels by neuroblastomas and other tumors of neuroectodermal origin, where its expression correlates with increased tumor progression and poor prognosis. Although established therapies with GD2-specific antibodies can be efficacious, more effective treatment options are needed for advanced and relapsed tumors. The aim of this work was the generation and functional evaluation of natural killer cells engineered with a GD2-specific chimeric antigen receptor (CAR) as a novel off-the-shelf adoptive immunotherapy approach. In preclinical in vitro models, these CAR-NK cells displayed high and selective cytotoxicity against GD2-expressing tumor cells. Moreover, GD2-CAR NK cells further modified to express an interleukin (IL)-15 superagonist displayed enhanced functionality also in the absence of exogenous cytokines and modulated proliferation and antitumor activity of surrounding innate immune cells and T lymphocytes. In contrast to T lymphocytes, natural killer (NK) cells do not require prior sensitization but are rapidly activated upon encountering virally infected or neoplastic cells. In addition, NK cells can be safely applied in an allogeneic setting, making them important effector cells for the development of off-the-shelf therapeutics for adoptive cancer immunotherapy. To further enhance their therapeutic potential, here, we engineered continuously expanding NK-92 cells as a clinically relevant model to express a humanized second-generation chimeric antigen receptor (CAR) with a composite CD28-CD3ζ signaling domain (hu14.18.28.z) that targets the disialoganglioside GD2, which is expressed at high levels by neuroblastoma cells and other tumors of neuroectodermal origin. In a separate approach, we fused an IL-15 superagonist (RD-IL15) to the GD2-CAR via a P2A processing site. Lentivirally transduced NK-92/hu14.18.28.z and NK-92/hu14.18.28.z_RD-IL15 cells both displayed high and stable CAR surface expression and specific cytotoxicity toward GD2-positive tumor cells. GD2-CAR NK cells carrying the RD-IL15 construct in addition expressed the IL-15 superagonist, resulting in self-enrichment and targeted cell killing in the absence of exogenous IL-2. Furthermore, co-culture with RD-IL15-secreting GD2-CAR NK cells markedly enhanced proliferation and cytotoxicity of bystander immune cells in a paracrine manner. Our results demonstrate that GD2-CAR NK cells co-expressing the IL-15 superagonist mediate potent direct and indirect antitumor effects, suggesting this strategy as a promising approach for the further development of functionally enhanced cellular therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is the predominant type of non-Hodgkin lymphoma—the most common haematological malignancy worldwide. These two cancers are cancers of the immune system and dyslipidemia is a hallmark of both cancer and inflammation. Cancer needs specific lipid species to sustain growth and survival. The global plasma lipidome and sub-lipidome of inflammatory pathways in DLBCL have not yet been reported. In order to address this gap, we conducted targeted lipidomics using liquid chromatography—multiple reaction monitoring to investigate bioactive plasma lipids involved in metabolic and signalling pathways of inflammation and immunity. The global lipidome change in plasma DLBCL was determined by four-dimensional trapped ion mobility mass spectrometry-based lipidomics. In our study, we observed differential lipid profiles in treatment-naïve female patients with DLBCL and disease-free controls. We suggest here the set of sphingosine 1-phosphate, sphingomyelins SM 36:1 and SM 34:1, and phosphatidylinositol PI 34:1 as DLBCL lipid signature, which could serve as a basis for the prospective validation in larger DLBCL cohorts. Lipidome dysregulation is a hallmark of cancer and inflammation. The global plasma lipidome and sub-lipidome of inflammatory pathways have not been reported in diffuse large B-cell lymphoma (DLBCL). In a pilot study of plasma lipid variation in female DLBCL patients and BMI-matched disease-free controls, we performed targeted lipidomics using LC-MRM to quantify lipid mediators of inflammation and immunity, and those known or hypothesised to be involved in cancer progression: sphingolipids, resolvin D1, arachidonic acid (AA)-derived oxylipins, such as hydroxyeicosatetraenoic acids (HETEs) and dihydroxyeicosatrienoic acids, along with their membrane structural precursors. We report on the role of the eicosanoids in the separation of DLBCL from controls, along with lysophosphatidylinositol LPI 20:4, implying notable changes in lipid metabolic and/or signalling pathways, particularly pertaining to AA lipoxygenase pathway and glycerophospholipid remodelling in the cell membrane. We suggest here the set of S1P, SM 36:1, SM 34:1 and PI 34:1 as DLBCL lipid signatures which could serve as a basis for the prospective validation in larger DLBCL cohorts. Additionally, untargeted lipidomics indicates a substantial change in the overall lipid metabolism in DLBCL. The plasma lipid profiling of DLBCL patients helps to better understand the specific lipid dysregulations and pathways in this cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the most common cancers worldwide, and novel treatments are urgently needed to improve treatment for cancer patients. In this report, three different designs of humanized EpCAM-CD3 antibodies were engineered and tested against colorectal tumors. The antibodies demonstrated high efficacy and specificity. In addition, the study demonstrates a novel method of delivering bispecific antibodies using mRNA-lipid nanoparticle (LNP) technology. The delivery of EpCAM-CD3 human Fc (hFc) mRNA-LNPs into mice tumors with intravenous T cell injection significantly blocked OVCAR-5 xenograft tumor growth in vivo. The data provide a basis for future clinical studies. The epithelial cell adhesion molecule (EpCAM) is often overexpressed in many types of tumors, including colorectal cancer. We sequenced and humanized an EpCAM mouse antibody and used it to develop bispecific EpCAM-CD3 antibodies. Three different designs were used to generate bispecific antibodies such as EpCAM-CD3 CrossMab knob-in-hole, EpCAM ScFv-CD3 ScFv (BITE), and EpCAM ScFv-CD3 ScFv-human Fc designs. These antibody designs showed strong and specific binding to the EpCAM-positive Lovo cell line and T cells, specifically killed EpCAM-positive Lovo cells and not EpCAM-negative Colo741 cells in the presence of T cells, and increased T cells' IFN-gamma secretion in a dose-dependent manner. In addition, transfection of HEK-293 cells with EpCAM ScFv-CD3 ScFv human Fc mRNA-LNPs resulted in antibody secretion that killed Lovo cells and did not kill EpCAM-negative Colo741 cells. The antibody increased IFN-gamma secretion against Lovo target cells and did not increase it against Colo741 target cells. EpCAM-CD3 hFc mRNA-LNP transfection of several cancer cell lines (A1847, C30, OVCAR-5) also demonstrated functional bispecific antibody secretion. In addition, intratumoral delivery of the EpCAM-CD3 human Fc mRNA-LNPs into OVCAR-5 tumor xenografts combined with intravenous injection of T cells significantly blocked xenograft tumor growth. Thus, EpCAM-CD3 hFc mRNA-LNP delivery to tumor cells shows strong potential for future clinical studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Overview of the onset and progression of B-cell lymphoma under infection with the hepatitis C virus, and a review of the current status of biomarkers related to treatment efficacy and prognosis under the progress of DAA therapy. The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed. [ABSTRACT FROM AUTHOR]

Simple Summary: As one of the most malignant cancers, the mechanisms underlying the occurrence and development of hepatocellular carcinoma (HCC) are complex, and the development of effective treatment strategies has been difficult. Extracellular vesicles (EVs) participate in HCC development in various ways. This review summarizes the latest research on EVs related to Wnt signaling in HCC and expounds on the underlying mechanisms, providing a reference for novel HCC treatment strategies. As the primary type of liver cancer, hepatocellular carcinoma (HCC) causes a large number of deaths every year. Despite extensive research conducted on this disease, the prognosis of HCC remains unclear. Recently, research has largely focused on extracellular vesicles (EVs), and they have been found to participate in various ways in the development of various diseases, including HCC, such as by regulating cell signaling pathways. However, recent studies have reported the mechanisms underlying the regulation of Wnt signaling by EVs in HCC, primarily focusing on the regulation of the canonical pathways. This review summarizes the current literature on the regulation of Wnt signaling by EVs in HCC and their underlying mechanisms. In addition, we also present future research directions in this field. This will deepen the understanding of HCC and provide new ideas for its treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The objective of the study was to investigate the possibility of lncRNA HCP5-encoded peptide/protein and the role of the resulting product in triple-negative breast cancer. Our study revealed that lncRNA HCP5 encodes a 132-amino acid sequence, referred to as HCP5-132aa, which enhances the growth of triple-negative breast cancer cells by regulating ferroptosis. Moreover, breast cancer patients with elevated levels of HCP5-132aa had a worse prognosis. Our findings have revealed a regulatory mechanism of ferroptosis in triple-negative breast cancer that is modulated by an lncRNA-encoded product. Background: Long non-coding RNAs (lncRNAs) are a class of RNA molecules that are longer than 200 nucleotides and were initially believed to lack encoding capability. However, recent research has found open reading frames (ORFs) within lncRNAs, suggesting that they may have coding capacity. Despite this discovery, the mechanisms by which lncRNA-encoded products are involved in cancer are not well understood. The current study aims to investigate whether lncRNA HCP5-encoded products promote triple-negative breast cancer (TNBC) by regulating ferroptosis. Methods: We used bioinformatics to predict the coding capacity of lncRNA HCP5 and conducted molecular biology experiments and a xenograft assay in nude mice to investigate the mechanism of its encoded products. We also evaluated the expression of the HCP5-encoded products in a breast cancer tissue microarray. Results: Our analysis revealed that the ORF in lncRNA HCP5 can encode a protein with 132-amino acid (aa), which we named HCP5-132aa. Further experiments showed that HCP5-132aa promotes TNBC growth by regulating GPX4 expression and lipid ROS level through the ferroptosis pathway. Additionally, we found that the breast cancer patients with high levels of HCP5-132aa have poorer prognosis. Conclusions: Our study suggests that overexpression of lncRNA HCP5-encoded protein is a critical oncogenic event in TNBC, as it regulates ferroptosis. These findings could provide new therapeutic targets for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Current treatments for patients with metastatic triple negative breast cancer (TNBC) are generally ineffective. This manuscript shows for the first time that the survival of mice with metastatic TNBC can be markedly increased through dietary manipulation. Our study revealed that the survival of some mice with metastatic TNBC was increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) are manipulated, and the levels of lipids are markedly reduced. The anticancer activity of this non-pharmacological strategy was higher than that of drugs currently used in the treatment of patients with metastatic TNBC. This anticancer strategy also increased the survival of mice with other types of metastatic cancers. Manipulation of AA and lipid levels with artificial diets may be a useful strategy to treat patients with metastatic TNBC and other types of disseminated cancer. Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were also tested in this model. AA manipulation led to modest improvements in mice survival when the levels of lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Some mice fed the artificial diets as monotherapy lived much longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the leading causes of cancer deaths worldwide. The use of nanoparticles as radiosensitizers and drug delivery vehicles could open the door to solving many of the obstacles in current cancer treatments. Gold nanoparticles (GNPs) and docetaxel (DTX) have shown very promising synergetic radiosensitization effects, despite DTX toxicity to normal tissues. In this paper, we explored the effect of a DTX prodrug encapsulated in lipid nanoparticles (LNPDTX-P) on GNP uptake in pancreatic cancer models in vitro and in vivo. The results show that LNPDTX-P-treated tumour samples have twice the amount of GNP uptake in both in vitro and in vivo models. These very promising results establish that LNPDTX-P have very similar outcomes to free DTX on tumour tissues. These results demonstrate the potential of incorporating GNPs and LNPDTX-P as radiosensitization tools to current radiotherapy protocols for improved tumour targeting. Current chemoradiation therapy suffers from normal tissue toxicity. Thus, we are proposing incorporating gold nanoparticles (GNPs) and docetaxel (DTX), as they have shown very promising synergetic radiosensitization effects. Here, we explored the effect of a DTX prodrug encapsulated in lipid nanoparticles (LNPDTX-P) on GNP uptake in pancreatic cancer models in vitro and in vivo. For the in vitro experiment, a pancreatic cancer cell line, MIA PaCa-2, was cultured and dosed with 1 nM GNPs and 45 nM free DTX or an equivalent dose of LNPDTX-P. For the in vivo experiment, MIA PaCa-2 cells were implanted subcutaneously in NRG mice, and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or an equivalent dose of LNPDTX-P. The results show that LNPDTX-P-treated tumour samples had double the amount GNPs compared to control samples, both in vitro and in vivo. The results are very promising, as LNPDTX-P have superior targeting of tumour tissues compared to free DTX due to their nanosize and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNPDTX-P could be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer (OC) is still the most lethal gynecological cancer due to late diagnosis when peritoneal metastasis has already occurred. OC progression requires lipid nutrients that are either synthesized endogenously in the cancer cells or imported from the surrounding host tissue. Accordingly, blockade of lipid synthesis has been shown to be a powerful strategy against OC. However, direct evidence of the role of lipid import and transport for OC cell growth is still largely missing. Therefore, we exposed OC cells to inhibitors of lipid uptake and transport proteins, which are typically overexpressed in OC. Our data reveal that pharmacological inhibition of these lipid handling proteins caused a drug-specific, dose-/time-dependent decline of lipid uptake, which was associated with cell growth reduction, cell cycle arrest, and apoptosis, indicating that OC cells are exquisitely sensitive to lipid deficiency. This dependency provides the rationale for the development of novel lipid-antimetabolic strategies against OC. Ovarian cancer (OC) is the most lethal gynecological malignancy with a 5-year survival rate of 49%. This is caused by late diagnosis when cells have already metastasized into the peritoneal cavity and to the omentum. OC progression is dependent on the availability of high-energy lipids/fatty acids (FA) provided by endogenous de novo biosynthesis and/or through import from the microenvironment. The blockade of these processes may thus represent powerful strategies against OC. While this has already been shown for inhibition of FA/lipid biosynthesis, evidence of the role of FA/lipid import/transport is still sparse. Therefore, we treated A2780 and SKOV3 OC cells with inhibitors of the lipid uptake proteins fatty acid translocase/cluster of differentiation 36 (FAT/CD36) and low-density lipoprotein (LDL) receptor (LDLR), as well as intracellular lipid transporters of the fatty acid-binding protein (FABP) family, fatty acid transport protein-2 (FATP2/SLC27A2), and ADP-ribosylation factor 6 (ARF6), which are overexpressed in OC. Proliferation was determined by formazan dye labeling/photometry and cell counting. Cell cycle analysis was performed by propidium iodide (PI) staining, and apoptosis was examined by annexin V/PI and active caspase 3 labeling and flow cytometry. RNA-seq data revealed altered stress and metabolism pathways. Overall, the small molecule inhibitors of lipid handling proteins BMS309403, HTS01037, NAV2729, SB-FI-26, and sulfosuccinimidyl oleate (SSO) caused a drug-specific, dose-/time-dependent inhibition of FA/LDL uptake, associated with reduced proliferation, cell cycle arrest, and apoptosis. Our findings indicate that OC cells are very sensitive to lipid deficiency. This dependency should be exploited for development of novel strategies against OC. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Due to the absence of specific early symptoms, most of CRC patients are often diagnosed at late stages. Different screening and diagnostic biomarkers are currently used for risk stratification and early detection of CRC, which might prolong the overall survival. High-throughput technologies have witnessed rapid advancements in the last decade. Consequently, the development of multiple omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, microbiomics, and lipidomics, has been widely applied to develop novel biomarkers that could contribute to the clinical management of CRC. In this paper, we aim to summarize the recent advances and future perspectives in using multi-omics technologies in CRC research, and reveal the potential implications of multi-omics for discovering novel biomarkers and enhancing clinical evaluations. Colorectal cancer (CRC) is common Cancer as well as the third leading cause of mortality around the world; its exact molecular mechanism remains elusive. Although CRC risk is significantly correlated with genetic factors, the pathophysiology of CRC is also influenced by external and internal exposures and their interactions with genetic factors. The field of CRC research has recently benefited from significant advances through Omics technologies for screening biomarkers, including genes, transcripts, proteins, metabolites, microbiome, and lipidome unbiasedly. A promising application of omics technologies could enable new biomarkers to be found for the screening and diagnosis of CRC. Single-omics technologies cannot fully understand the molecular mechanisms of CRC. Therefore, this review article aims to summarize the multi-omics studies of Colorectal cancer, including genomics, transcriptomics, proteomics, microbiomics, metabolomics, and lipidomics that may shed new light on the discovery of novel biomarkers. It can contribute to identifying and validating new CRC biomarkers and better understanding colorectal carcinogenesis. Discovering biomarkers through multi-omics technologies could be difficult but valuable for disease genotyping and phenotyping. That can provide a better knowledge of CRC prognosis, diagnosis, and treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GB) is an aggressive form of brain cancer with no effective cure. The current treatment for GB involves surgical removal of the tumor followed by chemotherapy and radiation therapy. However, GB develops chemo and radiation therapy resistance, leading to tumor recurrence. GB cells, in comparison to normal cells, have high metabolic rates and adapt several cell signaling pathways to promote their survival. Hence, identifying and inhibiting these tumor-protecting pathways can be helpful in managing GB therapy better. In this study, Spermidine/spermine N1-acetyltransferase 1 (SAT1), an enzyme known to cause resistance in GB cells, was targeted and inhibited. Lipid nanoparticles were designed and formulated to target and silence the SAT1 gene specifically. Inhibiting SAT1 in GB cells was toxic to the GB cells and further sensitized them towards radiation and chemotherapy. Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood–brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Men with metastatic castration-resistant prostate cancer (mCRPC) have shorter overall survival and resist therapy faster if their blood have a poor lipid profile. This poor lipid profile includes high levels of sphingolipids, thus reducing these sphingolipids may slow prostate cancer growth. The aim of our study is to determine if simvastatin can change a poor lipid profile (high sphingolipids) into a better profile (low sphingolipids) in mCRPC. Twenty-seven men with mCRPC were given simvastatin together with their standard treatment for 12 weeks. We found that 11 men had the poor lipid profile at the start of the study. After 12 weeks of treatment, 40% of these 11 men no longer had the poor lipid profile and their sphingolipids were reduced, regardless of changes in their blood cholesterol, LDL or triglycerides. In conclusion, simvastatin can modify the poor lipid profile in some men with mCRPC. Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23–52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is among the most common cancer types in both men and women, and its early detection significantly improves survival. Minimally-invasive blood- or urine-based tests may increase the RCC detection rate, especially before patients develop symptoms. Here, we report significant changes in concentrations of sulfatides and sphingomyelins in plasma and urine in RCC patients compared to healthy controls. For the first time, we present findings that similar alterations appear in the lipid profiles of body fluids and tissues in patients. We observe gradual changes in sulfatide and sphingomyelin concentrations with increasing tumor stage and grade. We built binary classifiers that detect RCC based on plasma and urine lipidome dysregulations, and we show that the plasma lipidome alterations enable distinguishing between early-stage RCC and controls. Our results demonstrate the considerable potential of lipid screening in biofluids for RCC detection and monitoring in clinical settings. Purpose: RCC, the most common type of kidney cancer, is associated with high mortality. A non-invasive diagnostic test remains unavailable due to the lack of RCC-specific biomarkers in body fluids. We have previously described a significantly altered profile of sulfatides in RCC tumor tissues, motivating us to investigate whether these alterations are reflected in collectible body fluids and whether they can enable RCC detection. Methods: We collected and further analyzed 143 plasma, 100 urine, and 154 tissue samples from 155 kidney cancer patients, together with 207 plasma and 70 urine samples from 214 healthy controls. Results: For the first time, we show elevated concentrations of lactosylsulfatides and decreased levels of sulfatides with hydroxylated fatty acyls in body fluids of RCC patients compared to controls. These alterations are emphasized in patients with the advanced tumor stage. Classification models are able to distinguish between controls and patients with RCC. In the case of all plasma samples, the AUC for the testing set was 0.903 (0.844–0.954), while for urine samples it was 0.867 (0.763–0.953). The models are able to efficiently detect patients with early- and late-stage RCC based on plasma samples as well. The test set sensitivities were 80.6% and 90%, and AUC values were 0.899 (0.832–0.952) and 0.981 (0.956–0.998), respectively. Conclusion: Similar trends in body fluids and tissues indicate that RCC influences lipid metabolism, and highlight the potential of the studied lipids for minimally-invasive cancer detection, including patients with early tumor stages, as demonstrated by the predictive ability of the applied classification models. [ABSTRACT FROM AUTHOR]

Simple Summary: We previously showed that breast tumor tissues from women display an imbalance in abundance and composition of microbiota compared to normal healthy breast tissues. It is unknown whether these differences in breast tumor microbiota may be driven by alterations in microbial metabolites, leading to potentially protective or pathogenic consequences. The aim of our study was to conduct global metabolic profiling on normal and breast tumor tissues to identify differences in metabolite profiles and to determine whether breast microbial dysbiosis may be associated with enrichment of microbial metabolites in triple-negative breast cancer (TNBC) which disproportionately affects women of African ancestry. We observed significant correlations between elevated lipid metabolism pathways and microbial dysbiosis in TNBC tissues from both non-Hispanic black and white women. This is the first study to report an association between breast microbial dysbiosis and alterations in host metabolic pathways in breast tumors, including TNBC, of non-Hispanic black and non-Hispanic white women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that is non-responsive to hormonal therapies and disproportionately impact women of African ancestry. We previously showed that TN breast tumors have a distinct microbial signature that differs from less aggressive breast tumor subtypes and normal breast tissues. However, it is unknown whether these differences in breast tumor microbiota may be driven by alterations in microbial metabolites, leading to potentially protective or pathogenic consequences. The goal of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in normal and breast tumor tissues, including TNBC, of non-Hispanic black (NHB) and non-Hispanic white (NHW) women. In this study, we profiled the microbiome (16S rRNA) from breast tumor tissues and analyzed 984 metabolites from a total of 51 NHB and NHW women. Breast tumor tissues were collected from 15 patients with TNBC, 12 patients with less aggressive luminal A-type (Luminal) breast cancer, and 24 healthy controls for comparison using UHPLC-tandem mass spectrometry. Principal component analysis and hierarchical clustering of the global metabolomic profiling data revealed separation between metabolic signatures of normal and breast tumor tissues. Random forest analysis revealed a unique biochemical signature associated with elevated lipid metabolites and lower levels of microbial-derived metabolites important in controlling inflammation and immune responses in breast tumor tissues. Significant relationships between the breast microbiome and the metabolome, particularly lipid metabolism, were observed in TNBC tissues. Further investigations to determine whether alterations in sphingolipid, phospholipid, ceramide, amino acid, and energy metabolism pathways modulate Fusobacterium and Tenericutes abundance and composition to alter host metabolism in TNBC are necessary to help us understand the risk and underlying mechanisms and to identify potential microbial-based targets. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival of organic systems is dependent on metabolic conditions, necessary for the proper functioning of all biological processes. Cancer takes advantage of altered bioenergetic circuits to improve its chances of growth, and pancreatic ductal adenocarcinoma is no exception. In this review, we describe the metabolic features of pancreatic ductal adenocarcinoma and discuss how this dependency could be exploited as a weakness for clinical interventions. Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the third-most diagnosed cancer and the second-leading cause of cancer-related deaths worldwide. Limitations in early and accurate diagnosis of CRC gives rise to poor patient survival. Advancements in analytical techniques have improved our understanding of the cellular and metabolic changes occurring in CRC and potentiate avenues for improved diagnostic and therapeutic strategies. Lipids are metabolites with important biological functions; however, their role in CRC is poorly understood. Here, we provide an in-depth review of the recent literature concerning lipid alterations in CRC and propose eight lipid metabolism-associated hallmarks of CRC. Lipids have diverse structures, with multifarious regulatory functions in membrane homeostasis and bioenergetic metabolism, in mediating functional protein–lipid and protein–protein interactions, as in cell signalling and proliferation. An increasing body of evidence supports the notion that aberrant lipid metabolism involving remodelling of cellular membrane structure and changes in energy homeostasis and signalling within cancer-associated pathways play a pivotal role in the onset, progression, and maintenance of colorectal cancer (CRC) and their tumorigenic properties. Recent advances in analytical lipidome analysis technologies have enabled the comprehensive identification and structural characterization of lipids and, consequently, our understanding of the role they play in tumour progression. However, despite progress in our understanding of cancer cell metabolism and lipidomics, the key lipid-associated changes in CRC have yet not been explicitly associated with the well-established 'hallmarks of cancer' defined by Hanahan and Weinberg. In this review, we summarize recent findings that highlight the role of reprogrammed lipid metabolism in CRC and use this growing body of evidence to propose eight lipid metabolism-associated hallmarks of colorectal cancer, and to emphasize their importance and linkages to the established cancer hallmarks. [ABSTRACT FROM AUTHOR]

Simple Summary: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a multifunctional tumor suppressor with protein- and lipid-phosphatase activities. The inactivation of PTEN is commonly found in all human cancers and is correlated with tumor progression. PTEN-lipid-phosphatase activity has been well documented to dephosphorylate phosphatidylinositol-3, 4, 5-phosphate (PIP3), which hinders cell growth and survival by dampening the PI3K and AKT signaling activity. PTEN-protein-phosphatase activity is less well studied and understood. Recent studies have reported that PTEN-protein-phosphatase activity dephosphorylates the different proteins and acts in various cell functions. We here review the PTEN mutations and protein-phosphatase substrates in tumor progression. We aim to address the gap in our understanding as to how PTEN protein phosphatase contributes to its tumor-suppression functions. PTEN is the second most highly mutated tumor suppressor in cancer, following only p53. The PTEN protein functions as a phosphatase with lipid- and protein-phosphatase activity. PTEN-lipid-phosphatase activity dephosphorylates PIP3 to form PIP2, and it then antagonizes PI3K and blocks the activation of AKT, while its protein-phosphatase activity dephosphorylates different protein substrates and plays various roles in tumorigenesis. Here, we review the PTEN mutations and protein-phosphatase substrates in tumorigenesis and metastasis. Our purpose is to clarify how PTEN protein phosphatase contributes to its tumor-suppressive functions through PI3K-independent activities. [ABSTRACT FROM AUTHOR]

Simple Summary: The indolent nature of some cancers makes early detection challenging, as such significant effort is placed on identifying circulating cancer biomarkers using minimally invasive, highly sensitive diagnostic assays. Biological fluids contain small extracellular vesicles including exosomes, which have many tissue origins. Cancer cells increase production and release of exosomes in the circulation to deliver biologically active compounds that can reprogram recipient cells, which potentially represent a valuable source of biomarkers. In this review, we evaluate the biogenesis of exosomes to understand how cancer cells alter their production and how their molecular cargoes interact with the microenvironment. Next, we provide a comprehensive inventory of techniques available for exosome purification, as this represents the most critical aspect for sensitive and specific evaluation of their biomarker content. Finally, we provide a current evaluation of their use as human cancer biomarkers. Although diagnostic and therapeutic treatments of cancer have tremendously improved over the past two decades, the indolent nature of its symptoms has made early detection challenging. Thus, inter-disciplinary (genomic, transcriptomic, proteomic, and lipidomic) research efforts have been focused on the non-invasive identification of unique "silver bullet" cancer biomarkers for the design of ultra-sensitive molecular diagnostic assays. Circulating tumor biomarkers, such as CTCs and ctDNAs, which are released by tumors in the circulation, have already demonstrated their clinical utility for the non-invasive detection of certain solid tumors. Considering that exosomes are actively produced by all cells, including tumor cells, and can be found in the circulation, they have been extensively assessed for their potential as a source of circulating cell-specific biomarkers. Exosomes are particularly appealing because they represent a stable and encapsulated reservoir of active biological compounds that may be useful for the non-invasive detection of cancer. T biogenesis of these extracellular vesicles is profoundly altered during carcinogenesis, but because they harbor unique or uniquely combined surface proteins, cancer biomarker studies have been focused on their purification from biofluids, for the analysis of their RNA, DNA, protein, and lipid cargoes. In this review, we evaluate the biogenesis of normal and cancer exosomes, provide extensive information on the state of the art, the current purification methods, and the technologies employed for genomic, transcriptomic, proteomic, and lipidomic evaluation of their cargoes. Our thorough examination of the literature highlights the current limitations and promising future of exosomes as a liquid biopsy for the identification of circulating tumor biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor hypoxia remains a significant problem in the effective treatment of most cancers. Tumor cells within hypoxic niches tend to be largely resistant to most therapeutic modalities, and adaptation of the cells within the hypoxic microenvironment imparts the cells with aggressive, invasive behavior. Thus, a major goal of successful cancer therapy should be the eradication of hypoxic tumor cells. Carbonic Anhydrase IX (CAIX) is an exquisitely hypoxia induced protein, selectively expressed on hypoxic tumor cells, and thus has garnered significant attention as a therapeutic target. In this Commentary, we discuss the current status of targeting CAIX, and future strategies for effective, durable cancer treatment. Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The newly described form of iron-dependent cell death, called ferroptosis, has emerged as a powerful strategy for eradicating cancer cells. This is of particular importance for pancreatic ductal adenocarcinoma (PDAC), which has been shown to be one of the most aggressive tumors, with a five-year overall survival of less than 8%. The aim of the present study is to identify the most potent and selective target for the induction of ferroptosis in PDAC cells. The results presented here are of great importance not only for the development of novel and more effective anti-cancer therapeutics, but also anticipate potential resistant mechanisms that cancer cells might deploy. This way, ferroptosis-based therapeutics may be a step ahead of highly adaptable cancer cells. The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention. [ABSTRACT FROM AUTHOR]

Simple Summary: Basal cell carcinoma (BCC) belongs to one of the most common types of skin carcinoma characterized by high morbidity worldwide. Available therapies are mainly based on non-targeted approaches, which encounter a significant risk of systemic toxicity in several organs. In this work, we discuss a novel approach using targeted therapy-based lipid nanoparticles loaded with classical chemotherapeutic drugs, Hedgehog inhibitors, or photosensitizers for improved localized therapy while reducing adverse side effects and systemic toxicity. New therapeutic topical strategies are presented despite the limited number of reports available. Skin cancer is the most common type of carcinoma diagnosed worldwide, with significant morbidity and mortality rates among Caucasians, in particular basal cell carcinoma (BCC). The main risk factors of BCC are well-identified, and there are many chemotherapeutic drugs available for its treatment. The effectiveness of therapeutic options is governed by several factors, including the location of the tumor, its size, and the presence of metastases (although rare for BCC). However, available treatments are based on non-targeted approaches, which encounter a significant risk of systemic toxicity in several organs. Site-specific chemotherapy for BCC has been proposed via the loading of anticancer drugs into nanoparticles. Among various types of nanoparticles, in this review, we focus on potential new regimens for the treatment of BCC using classical anticancer drugs loaded into novel lipid nanoparticles. To meet patient aesthetic expectations and enhance the effectiveness of basal cell carcinoma treatment, new therapeutic topical strategies are discussed, despite a limited number of reports available in the literature. [ABSTRACT FROM AUTHOR]

Simple Summary: BRAF is a serine/threonine kinase that is commonly mutated across cancers. The BRAF V600E mutation is targetable with kinase inhibitors; however, many patients eventually develop resistance. Recent evidence suggests that tumors harboring BRAF mutations may oxidize fatty acids for energy rather than utilizing aerobic glycolysis (the Warburg effect). Understanding the metabolism of cells harboring BRAF mutations may uncover targets to improve therapy response. We studied the effects of BRAF mutation and expression on metabolism. We found that cell expressing BRAF V600E were enriched with immunomodulatory lipids and have a metabolism that is distinct from cells expressing wild type BRAF. We also found that patients with melanoma who did not respond to BRAF-targeted therapy had plasma lipid profiles that were different from patients who responded to this therapy. Overall, our findings indicate that targeting lipid metabolism may be a potential alternative strategy to improve patient responses to BRAF-targeted therapies. There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Germline loss-of-function mutations in any of over 20 known Fanconi anemia (FA) genes cause the disorder FA. The FA pathway plays a key role in the repair of DNA interstrand crosslinks (ICLs) and stabilization of stalled replication fork. Epidemiological studies have shown that persons with FA have a uniquely increased susceptibility to squamous cell carcinomas (SCCs) and increased human papilloma virus (HPV) prevalence. Genomic and transcriptomic studies are informative, but there is a paucity of data regarding metabolic deregulation in FA deficient systems. Metabolism is an essential component of cancer development and has significant impact on therapeutic outcomes. Therefore, a deeper understanding of the metabolic architecture of FA may aid in our understanding of SCC development, and allow for the discovery of metabolism-based diagnostic biomarkers and new therapeutic targets. In this review, we discuss known metabolic consequences of FA pathway loss on cancer pathogenesis, and in particular in normal and transformed keratinocytes—the cells of origin for SCC. Fanconi anemia (FA) is a rare inherited, generally autosomal recessive syndrome, but it displays X-linked or dominant negative inheritance for certain genes. FA is characterized by a deficiency in DNA damage repair that results in bone marrow failure, and in an increased risk for various epithelial tumors, most commonly squamous cell carcinomas of the head and neck (HNSCC) and of the esophagus, anogenital tract and skin. Individuals with FA exhibit increased human papilloma virus (HPV) prevalence. Furthermore, a subset of anogenital squamous cell carcinomas (SCCs) in FA harbor HPV sequences and FA-deficient laboratory models reveal molecular crosstalk between HPV and FA proteins. However, a definitive role for HPV in HNSCC development in the FA patient population is unproven. Cellular metabolism plays an integral role in tissue homeostasis, and metabolic deregulation is a known hallmark of cancer progression that supports uncontrolled proliferation, tumor development and metastatic dissemination. The metabolic consequences of FA deficiency in keratinocytes and associated impact on the development of SCC in the FA population is poorly understood. Herein, we review the current literature on the metabolic consequences of FA deficiency and potential effects of resulting metabolic reprogramming on FA cancer phenotypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is a heterogenous disease in terms of disease aggressiveness and therapy response, leading to dilemmas in treatment decisions. This heterogeneity reflects the multifocal nature of prostate cancer and its diversity in cellular and molecular composition, necessitating spatial molecular approaches. Here in view of the emerging importance of rewired lipid metabolism as a source of biomarkers and therapeutic targets for prostate cancer, we highlight recent advancements in technologies that enable the spatial mapping of lipids and related metabolic pathways associated with prostate cancer development and progression. We also evaluate their potential for future implementation in treatment decision-making in the clinical management of prostate cancer. Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management; the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy. In part, this lack of progress reflects the inherent challenge of undertaking target and biomarker discovery in clinical prostate tumours, which are cellularly heterogeneous and multifocal, necessitating the use of spatial analytical approaches. In this review, the principles of mass spectrometry-based lipid imaging and complementary gene-based spatial omics technologies, their application to prostate cancer and recent advancements in these technologies are considered. We put in perspective studies that describe spatially-resolved lipid maps and metabolic genes that are associated with prostate tumours compared to benign tissue and increased risk of disease progression, with the aim of evaluating the future implementation of spatial lipidomics and complementary transcriptomics for prognostication, target identification and treatment decision-making for prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarizes the current knowledge on mesothelin's function, its role in cancer, and opportunities for immunotherapeutic targeting of mesothelin. Immunotherapies including monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK-cells, targeted alpha therapies, and bispecific T cell engaging molecules are reviewed. We show future directions for mesothelin targeting in hematological malignancies, including acute myeloid leukemia. Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, and most recently in hematological malignancies, including acute myeloid leukemia (AML). Although the function of mesothelin is widely unknown, interactions with MUC16/CA125 indicate that mesothelin plays a role in the regulation of proliferation, growth, and adhesion signaling. Most research on mesothelin currently focuses on utilizing mesothelin to design targeted cancer therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK cells, bispecific T cell engaging molecules, and targeted alpha therapies, amongst others. Both in vitro and in vivo studies using different immunotherapeutic modalities in mesothelin-positive AML models highlight the potential impact of this approach as a unique opportunity to treat hard-to-cure AML. [ABSTRACT FROM AUTHOR]

The members of the PhosphoInositide-3 Kinase (PI3K) protein family are well-known regulators of proliferative signals. By the generation of lipid second messengers, they mediate the activation of AKT/PKB (AKT) and mammalian Target Of Rapamycin (mTOR) pathways. Although mutations in the PI3K/AKT/mTOR pathway are highly characterized in cancer, recent evidence indicates that alterations in the proliferative signals are major drivers of other diseases such as overgrowth disorders and polycystic kidney disease. In this review, we briefly summarize the role of the PI3K/AKT/mTOR pathway in cell proliferation by comparing the effect of alterations in PI3K enzymes in different tissues. In particular, we discuss the most recent findings on how the same pathway may lead to different biological effects, due to the convergence and cooperation of different signaling cascades. [ABSTRACT FROM AUTHOR]

Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation. [ABSTRACT FROM AUTHOR]

Simple Summary: The carbohydrate moiety of cell surface glycolipids is modified in cancers of neuro–ectoderm origin, leading to the expression of more complex structures with two or more sialic acid residues. These alterations result from the upregulation of the ST8SIA1 gene that encodes GD3 synthase, the enzyme controlling the biosynthesis of complex gangliosides, and are usually associated with a more aggressive phenotype and a poor outcome for patients, making GD3 synthase an interesting target for cancer therapy. This review reports our general knowledge of GD3 synthase gene expression and regulation, its role in both epithelial–mesenchymal transition (EMT) and cancer progression, and the different approaches targeting GD3S expression in cancers. GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuro–ectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelial–mesenchymal transition. Since GD3 and GD2 levels are directly linked to GD3 synthase expression and activity, targeting GD3 synthase appears to be a promising strategy through which to interfere with ganglioside-associated malignant properties. We review here the current knowledge on GD3 synthase expression and regulation in cancers, and the consequences of complex ganglioside expression on cancer cell signaling and properties, highlighting the relationships between GD3 synthase expression and epithelial–mesenchymal transition and stemness. Different strategies were used to modulate GD3 synthase expression in cancer cells in vitro and in animal models, such as inhibitors or siRNA/lncRNA, which efficiently reduced cancer cell malignant properties and the proportion of GD2 positive cancer stem cells, which are associated with high metastatic properties, resistance to therapy, and cancer relapse. These data show the relevance of targeting GD3 synthase in association with conventional therapies, to decrease the number of cancer stem cells in tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Developing new anticancer medicaments is focused on inducing controlled elimination of tumor tissue without severe side effects. It is essential to enable the medicament to reach the target molecule without provoking the immune response too early. The first cellular changes might occur already at the level of the cell membrane, composed mainly of lipids. Therefore, we used spectroscopic techniques to study the interaction of potential metallodrug [Ru(η5-C5H5)(PPh3)2CN] (RuCN) with lipids of A2780 ovarian cancer cells and investigated if these changes are affected by the presence of drug carriers (carbon dots (CDs) and nitrogen-doped carbon dots (N-CDs)). Our results showed that CDs and N-CDs prevent lysis and moderate oxidative stress of lipids caused by metallodrug, still keeping the antitumor activity and potential to penetrate through the lipid bilayer. Therefore, Ru drug loading to carriers balances the anticancer efficiency and leads to better anticancer outcomes by reducing the oxidative stress that has been linked to cancer progression. In the last decade, targeting membrane lipids in cancer cells has been a promising approach that deserves attention in the field of anticancer drug development. To get a comprehensive understanding of the effect of the drug [Ru(η5-Cp)(PPh3)2CN] (RuCN) on cell lipidic components, we combine complementary analytical approaches, matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI TOF MS) and synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectroscopy. Techniques are used for screening the effect of potential metallodrug, RuCN, without and with drug carriers (carbon dots (CDs) and nitrogen-doped carbon dots (N-CDs)) on the lipids of the human ovarian cancer cell line A2780. MALDI TOF MS results revealed that the lysis of ovarian cancer membrane lipids is promoted by RuCN and not by drug carriers (CDs and N-CDs). Furthermore, SR-FTIR results strongly suggested that the phospholipids of cancer cells undergo oxidative stress after the treatment with RuCN that was accompanied by the disordering of the fatty acid chains. On the other hand, using (N-)CDs as RuCN nanocarriers prevented the oxidative stress caused by RuCN but did not prevent the disordering of the fatty acid chain packing. Finally, we demonstrated that RuCN and RuCN/(N-)CDs alter the hydration of the membrane surface in the membrane–water interface region. [ABSTRACT FROM AUTHOR]

Simple Summary: Rapidly proliferating cancer cells reprogram lipid metabolism to keep the balance between fatty acid uptake, synthesis, consumption, and storage as triacylglycerides (TAG). Acylglycerolphosphate acyltransferases (AGPATs)/lysophosphatidic acid acyltransferases (LPAATs) are a family of enzymes that catalyze the synthesis of phosphatidic acid (PA), an intermediate in TAG synthesis, a signaling molecule, and a precursor of phospholipids. Importantly, the expression of AGPATs has been linked to diverse physiological and pathological phenotypes, including cancer. In this review, we present an overview of lipid metabolism reprogramming in cancer cells and give insight into the expression of AGPAT isoforms as well as their association with cancers, parameters of tumor biology, patient classification, and prognosis. Altered lipid metabolism is an emerging hallmark of aggressive tumors, as rapidly proliferating cancer cells reprogram fatty acid (FA) uptake, synthesis, storage, and usage to meet their increased energy demands. Central to these adaptive changes, is the conversion of excess FA to neutral triacylglycerides (TAG) and their storage in lipid droplets (LDs). Acylglycerolphosphate acyltransferases (AGPATs), also known as lysophosphatidic acid acyltransferases (LPAATs), are a family of five enzymes that catalyze the conversion of lysophosphatidic acid (LPA) to phosphatidic acid (PA), the second step of the TAG biosynthesis pathway. PA, apart from its role as an intermediate in TAG synthesis, is also a precursor of glycerophospholipids and a cell signaling molecule. Although the different AGPAT isoforms catalyze the same reaction, they appear to have unique non-overlapping roles possibly determined by their distinct tissue expression and substrate specificity. This is best exemplified by the role of AGPAT2 in the development of type 1 congenital generalized lipodystrophy (CGL) and is also manifested by recent studies highlighting the involvement of AGPATs in the physiology and pathology of various tissues and organs. Importantly, AGPAT isoform expression has been shown to enhance proliferation and chemoresistance of cancer cells and correlates with increased risk of tumor development or aggressive phenotypes of several types of tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: This study shows the potential of a novel dendritic cell vaccine therapy in antitumor immunity, in which bone marrow-derived dendritic cells are electroporated with an exogenous ovalbumin protein and simultaneously pulsed with α-galactosylceramide. This strategy enhances the induction of cytotoxic CD8+ T cells specific for tumor-associated antigens through the activation of invariant natural killer T cells, natural killer cells, and intrinsic dendritic cells. Moreover, this strategy sustains antigen-specific antitumor T cell responses over time. (1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of nucleic acid drugs has progressed in recent years, especially in the field of cancer therapy, where there has been considerable progress in the development of siRNA-, antisense oligonucleotide-, and miRNA-related drugs. Extracellular vesicles are expected to play a pivotal role as a drug delivery system for nucleic acid drugs. By conjugating EVs with proteins, antibodies, or chemical antibodies called aptamers that specifically bind to cancer, EVs can be effectively delivered to tumor tissues and cells. This review summarizes the latest findings, serving as a bridge to the clinical application of nucleic acid drugs in cancer therapy. Nucleic acid drugs, such as siRNAs, antisense oligonucleotides, and miRNAs, exert their therapeutic effects by causing genetic changes in cells. However, there are various limitations in their delivery to target organs and cells, making their application to cancer treatment difficult. Extracellular vesicles (EVs) are lipid bilayer particles that are released from most cells, are stable in the blood, and have low immunogenicity. Methods using EVs to deliver nucleic acid drugs to target organs are rapidly being developed that take advantage of these properties. There are two main methods for loading nucleic acid drugs into EVs. One is to genetically engineer the parent cell and load the target gene into the EV, and the other is to isolate EVs and then load them with the nucleic acid drug. Target organ delivery methods include passive targeting using the enhanced permeation and retention effect of EVs and active targeting in which EVs are modified with antibodies, peptides, or aptamers to enhance their accumulation in tumors. In this review, we summarize the advantages of EVs as a drug delivery system for nucleic acid drugs, the methods of loading nucleic acid drugs into EVs, and the targeting of EVs to target organs. [ABSTRACT FROM AUTHOR]

Simple Summary: Previously, we have demonstrated that lipid and lipoprotein profiles in breast cancer patients are altered compared to a control showing a new link between triglycerides enriched particles and breast cancer, hence suggesting an active role of lipids and their metabolism in this pathology. In this study, we have demonstrated the importance of tumor microenvironment crosstalk as well as the crucial role of lipid transfer between adipose tissue and cancerous cells. Moreover, we have demonstrated that each breast cancer subtype has their specific lipid signature. Interestingly, drug resistant luminal A cell lines switch this metabolic profile to the triple negative lipid signature. Knowledge of these signatures might help us to understand how these specific lipids are related with drug resistance and how it may clarify new treatments in these cancer patients. Obesity and adipose tissue have been closely related to a poor cancer prognosis, especially in prostate and breast cancer patients. The ability of transferring lipids from the adipose tissue to the tumor cells is actively linked to tumor progression. However, different types of breast tumor seem to use these lipids in different ways and metabolize them in different pathways. In this study we have tracked by mass spectrometry how palmitic acid from the adipocytes is released to media being later incorporated in different breast cancer cell lines (MDA-MB-231, SKBR3, BT474, MCF-7 and its resistant MCF-7 EPIR and MCF-7 TAXR). We have observed that different lines metabolize the palmitic acid in a different way and use their carbons in the synthesis of different new lipid families. Furthermore, we have observed that the lipid synthesis pattern varied according to the cell line. Surprisingly, the metabolic pattern of the resistant cells was more related to the TNBC cell line compared to their sensitive cell line MCF-7. These results allow us to determine a specific lipid pattern in different cell lines that later might be used in breast cancer diagnosis and to find a better treatment according to the cancer molecular type. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is globally ranked as the sixth most diagnosed cancer, and the second most deadly cancer. To worsen matters, there are only limited therapeutic options currently available; therefore, it is necessary to find a reservoir from which new HCC treatments may be acquired. The field of phytomedicine may be the solution to this problem, as it offers an abundance of plant-derived molecules, which show capabilities of being effective against HCC proliferation, invasion, migration, and metastasis. In our review, we collect and analyze current evidence regarding these promising phytochemical effects on HCC, and delve into their potential as future chemotherapies. Additionally, information on the signaling behind these numerous phytochemicals is provided, in an attempt to understand their mechanisms. This review makes accessible the current body of knowledge pertaining to phytochemicals as HCC treatments, in order to serve as a reference and inspiration for further research into this subject. Hepatocellular carcinoma (HCC) is the most abundant form of liver cancer. It accounts for 75–85% of liver cancer cases and, though it ranks globally as the sixth most common cancer, it ranks second in cancer-related mortality. Deaths from HCC are usually due to metastatic spread of the cancer. Unfortunately, there are many challenges and limitations with the latest HCC therapies and medications, making it difficult for patients to receive life-prolonging care. As there is clearly a high demand for alternative therapy options for HCC, it is prudent to turn to plants for the solution, as their phytochemicals have long been used and revered for their many medicinal purposes. This review explores the promising phytochemical compounds identified from pre-clinical and clinical trials being used either independently or in conjunction with already existing cancer therapy treatments. The phytochemicals discussed in this review were classified into several categories: lipids, polyphenols, alkaloids, polysaccharides, whole extracts, and phytochemical combinations. Almost 80% of the compounds failed to progress into clinical studies due to lack of information regarding the toxicity to normal cells and bioavailability. Although large obstacles remain, phytochemicals can be used either as an alternative or integrative therapy in conjunction with existing HCC chemotherapies. In conclusion, phytochemicals have great potential as treatment options for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Different drugs, including antiproliferative and corticosteroids in general, are recommended for the treatment of hyperproliferative skin diseases (HSD). The effectiveness of many of these drugs is limited due to their low solubility in water and low penetration in the skin. The loading of these drugs in lipid nanocarriers, such as lipid nanoparticles and liposomes, has been considered as a successful solution to improve the drug bioavailability through the skin, to control their release kinetics and thus reduce the risk of potential side effects. In this work, we discuss the use of lipid nanocarriers loading drugs against HSD. Hyperproliferative skin diseases (HSD) are a group of diseases that include cancers, pre-cancerous lesions and diseases of unknown etiology that present different skin manifestations in terms of the degree and distribution of the injuries. Anti-proliferative agents used to treat these diseases are so diverse, including 5-aminolevulinic acid, 5-fluorouracil, imiquimod, methotrexate, paclitaxel, podophyllotoxin, realgar, and corticosteroids in general. These drugs usually have low aqueous solubility, which consequently decreases skin permeation. Thus, their incorporation in lipid nanocarriers has been proposed with the main objective to increase the effectiveness of topical treatment and reduce side effects. This manuscript aims to describe the advantages of using lipid nanoparticles and liposomes that can be used to load diversity of chemically different drugs for the treatment of HSD. [ABSTRACT FROM AUTHOR]

Simple Summary: Alkaloids are natural products that possess numerous pharmacological activities and have been exploited effectively to treat cancer. However, the clinically approved anticancer alkaloids are generally limited by serious side effects due to their lack of specificity to cancer cells, indiscriminate tissue distribution and toxic formulation excipients. Lipid-based nanoparticles represent the most effective drug delivery system concerning clinical translation owing to their unique appealing characteristics for drug delivery. This review aims to assess the potential of different types of lipid-based nanoparticles in encapsulating anticancer alkaloids. Our review shows that alkaloids encapsulated in lipid-based nanoparticles generally displayed an enhanced efficacy and toxicity profile than unencapsulated alkaloids in various cancers. Encapsulated alkaloids also demonstrated the ability to overcome multidrug resistance in cell lines and animal models. These findings support the broad application of lipid-based nanoparticles to encapsulate anticancer alkaloids and facilitate their clinical translation. Since the commercialization of morphine in 1826, numerous alkaloids have been isolated and exploited effectively for the betterment of mankind, including cancer treatment. However, the commercialization of alkaloids as anticancer agents has generally been limited by serious side effects due to their lack of specificity to cancer cells, indiscriminate tissue distribution and toxic formulation excipients. Lipid-based nanoparticles represent the most effective drug delivery system concerning clinical translation owing to their unique, appealing characteristics for drug delivery. To the extent of our knowledge, this is the first review to compile in vitro and in vivo evidence of encapsulating anticancer alkaloids in lipid-based nanoparticles. Alkaloids encapsulated in lipid-based nanoparticles have generally displayed enhanced in vitro cytotoxicity and an improved in vivo efficacy and toxicity profile than free alkaloids in various cancers. Encapsulated alkaloids also demonstrated the ability to overcome multidrug resistance in vitro and in vivo. These findings support the broad application of lipid-based nanoparticles to encapsulate anticancer alkaloids and facilitate their clinical translation. The review then discusses several limitations of the studies analyzed, particularly the discrepancies in reporting the pharmacokinetics, biodistribution and toxicity data. Finally, we conclude with examples of clinically successful encapsulated alkaloids that have received regulatory approval and are undergoing clinical evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: High-grade serous carcinoma (HGSOC) is the most aggressive subtype of ovarian cancer and accounts for the vast majority of advanced stage cases. Intracellular accumulation of lipids as lipid droplets has been recognized as one of the characteristics of cancers and implicated in poor prognosis of several cancers, such as human melanomas. Here, we investigated the relationship between prognosis and lipid accumulation in HGSOC, and found that enhanced lipid accumulation in HGSOC tissues significantly correlated with poor prognosis. In cell-based assays with human ovarian cancer cells, we provide evidence that aerobic glycolysis, which is one of the characteristic metabolic abnormalities in cancer, induced lipid accumulation within cancer cells and targeting the lipid accumulation could suppress cancer cell proliferation. Thus, our results propose abnormal lipid accumulation as a negative indicator of HGSOC prognosis and a novel therapeutic target. High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to explore metabolic remodeling in plasma and tissue samples in patients with glioblastoma through an integrated targeted and untargeted metabolomics-based strategy. We report phospholipids, sphingomyelins, acylcarnitines, and acylglycerols as key impaired metabolic classes in glioblastoma. (1) Background: Glioblastoma is the most common malignant brain tumor in adults. Its etiology remains unknown in most cases. Glioblastoma pathogenesis consists of a progressive infiltration of the white matter by tumoral cells leading to progressive neurological deficit, epilepsy, and/or intracranial hypertension. The mean survival is between 15 to 17 months. Given this aggressive prognosis, there is an urgent need for a better understanding of the underlying mechanisms of glioblastoma to unveil new diagnostic strategies and therapeutic targets through a deeper understanding of its biology. (2) Methods: To systematically address this issue, we performed targeted and untargeted metabolomics-based investigations on both tissue and plasma samples from patients with glioblastoma. (3) Results: This study revealed 176 differentially expressed lipids and metabolites, 148 in plasma and 28 in tissue samples. Main biochemical classes include phospholipids, acylcarnitines, sphingomyelins, and triacylglycerols. Functional analyses revealed deep metabolic remodeling in glioblastoma lipids and energy substrates, which unveils the major role of lipids in tumor progression by modulating its own environment. (4) Conclusions: Overall, our study demonstrates in situ and systemic metabolic rewiring in glioblastoma that could shed light on its underlying biological plasticity and progression to inform diagnosis and/or therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Lipids (fatty substances) and cytokines are molecules that affect how the immune response works. The measurement of the amounts of lipids and cytokines in blood might give clues about how prostate cancers grow or respond to treatment. This study looked at the blood levels of lipids and cytokines in men with advanced prostate cancer that was growing despite standard treatment (metastatic castration-resistant prostate cancer, mCRPC). We found that certain lipids were consistently associated with poorer clinical outcome, while cytokines were not. The levels of a type of lipid (ceramide) were associated with some cytokines. This lipid is known to activate the immune system and is associated with poor outcomes in mCRPC. A change in lipid profiles was associated with better response to treatment. Overall, our findings suggest that blood lipids might be more informative than cytokines, might influence the immune response, and might help predict treatment response. Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions. [ABSTRACT FROM AUTHOR]