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Ferroptosis is a nonapoptotic form of cell death characterized by iron‐dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis‐targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6‐methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis‐targeted therapies in the context of human health and disease. [ABSTRACT FROM AUTHOR]

Background: Awareness of age‐related features of carcinogenesis and the importance of cellular immunity is crucial for developing effective antitumor therapies for specific patient groups. Methods: In this study, we examined different populations of cancer stem cells (CSCs) and circulating tumor cells (CTCs) in "young" (8‐10 weeks) and "aged" (80‐82 weeks) C57BL/6 male mice. We used an orthotopic model of Lewis lung carcinoma (LLC) to evaluate the effectiveness of cell therapy targeting lung cancer through reprogrammed CD8‐positive T cells (rCD8+ T cells) in mice from two different ages. Results: The findings revealed that tumor progression with age is primarily caused by impaired recruitment of T cells to the lungs. Additionally, a lower number of CTCs and CSCs were observed in younger mice compared to the older mice. The antitumor effect of rCD8+ T cells in aged mice was found to be inferior to that in young mice, which can be attributed to the reduced impact of therapy on specific CSCs populations. Conclusions: These results offer new insights into the treatment of lung cancer using rCD8+ T cells. Considering the age‐related characteristics influencing disease progression, this therapy has the potential to significantly enhance the effectiveness of treatment methods. [ABSTRACT FROM AUTHOR]

This research aims to investigate the impact of Didang decoction (DD) on the formation of neutrophil extracellular traps (NETs) and cancer‐associated thrombosis in lung cancer. BALB/c nude mice were used to establish xenograft models for inducing deep vein thrombosis. Tumor growth and thrombus length were assessed. The impact of DD on NET generation was analyzed using enzyme‐linked immunosorbent assay, immunofluorescence staining, quantitative real‐time PCR, and western blot analysis, both in vivo and in vitro. CI‐amidine, a PAD4 inhibitor, was employed to evaluate the role of PAD4 in the generation of NETs. In vivo studies demonstrated that treatment with DD reduced tumor growth, inhibited thrombus formation, and decreased the levels of NET markers in the serum, tumor tissues, neutrophils, and thrombus tissues of mice. Additional data indicated that DD could suppress neutrophil counts, the release of tissue factor (TF), and the activation of thrombin‐activated platelets, all of which contributed to increased formation of NETs in mouse models. In vitro, following incubation with conditioned medium (CM) derived from Lewis lung carcinoma cells, the expression of NET markers in neutrophils was significantly elevated, and an extracellular fibrous network structure was observed. Nevertheless, these NET‐associated changes were partially counteracted by DD. Additionally, CI‐amidine reduced the expression of NET markers in CM‐treated neutrophils, consistent with the effects of DD. Collectively, DD inhibits cancer‐associated thrombosis in lung cancer by decreasing PAD4‐dependent NET formation through the regulation of TF‐mediated thrombin‐platelet activation. This presents a promising therapeutic strategy for preventing and treating venous thromboembolism in lung cancer. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis plays an important role in the occurrence and development of non‐small cell lung cancer (NSCLC). The atypical mitogen‐activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear. Methods: Adult male C57BL/6 wild‐type mice were randomly divided into the control group and p‐siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on. Results: We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c‐Jun n‐terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo. Conclusion: Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC. [ABSTRACT FROM AUTHOR]

The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors. [ABSTRACT FROM AUTHOR]

Angiogenesis is a complex process that involves the expansion of the pre‐existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis. [ABSTRACT FROM AUTHOR]

Background: Cancer cachexia is a debilitating syndrome associated with marked body loss because of muscular atrophy and fat loss. There are several mechanisms contributing to the pathogenesis of cachexia. The presence of the tumor releases cytokines from inflammatory and immune cells, which play a significant role in activating and deactivating certain pathways associated with protein, carbohydrate, and lipid metabolism. This review focuses on various cascades involving an imbalance between protein synthesis and degradation in the skeletal muscles. Objectives: This study aimed to elucidate the mechanisms involved in skeletal muscle wasting phenomenon over the last few years. Methods: This article briefly overviews different pathways responsible for muscle atrophy in cancer cachexia. Studies published up to April 2023 were included. Important findings and study contributions were chosen and compiled using several databases including PubMed, Google Scholar, Science Direct, and ClinicalTrials.gov using relevant keywords. Results: Cancer cachexia is a complex disease involving multiple factors resulting in atrophy of skeletal muscles. Systemic inflammation, altered energy balance and carbohydrate metabolism, altered lipid and protein metabolism, and adipose tissue browning are some of the major culprits in cancer cachexia. Increased protein degradation and decreased protein synthesis lead to muscle atrophy. Changes in signaling pathway like ubiquitin‐proteasome, autophagy, mTOR, AMPK, and IGF‐1 also lead to muscle wasting. Physical exercise, nutritional supplementation, steroids, myostatin inhibitors, and interventions targeting on inflammation have been investigated to treat cancer cachexia. Some therapy showed positive results in preclinical and clinical settings, although more research on the efficacy and safety of the treatment should be done. Conclusion: Muscle atrophy in cancer cachexia is the result of multiple complex mechanisms; as a result, a lot more research has been done to describe the pathophysiology of the disease. Targeted therapy and multimodal interventions can improve clinical outcomes for patients. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of programmed cell death driven by iron‐dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal‐based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir‐Bet) was developed by a metal‐ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir‐Cp*) species as Ir‐Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa‐B (NF‐κB) activation of Ir‐Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir‐Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs). [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe2+; ferrous) or oxidized (Fe3+; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5–IRP2 axis, a ubiquitin‐dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin‐dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor‐bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth. [ABSTRACT FROM AUTHOR]

Background: Fibroblast activation protein‐α (FAP) and livin α are considered as cancer‐associated fibroblasts (CAFs) and tumor‐specific targets, respectively, for immunogenic tumor vaccines. This study is designed to decipher the antitumor effect of double‐gene modified dendritic cells (DCs) on Lewis lung carcinoma (LLC). Methods: By encoding mouse FAP cDNA and human livin α (i.e., hlivin α) cDNA into recombinant adenoviral vector (rAd), rAd‐FAP, rAd‐hlivin α, and rAd‐FAP/hlivin α were constructed, which were then transduced into mouse DCs. LLC‐bearinig mice were immunized with the infected DCs (5 × 105 cells/mouse), followed by calculation of tumor volume and survival rate. The identification of CAFs from mouse LLC as well as the determination on expressions of FAP and livin α, was accomplished by western blot. Cytotoxic T lymphocyte assay was harnessed to assess the effect of the infected DCs on inducing splenic lymphocytes to lyse CAFs. Results: DCs were successfully transduced with rAd‐FAP/hlivin α in vitro. FAP was highly expressed in CAFs. CAFs were positive for α‐SMA and negative for CD45 and CD31. Livin α level was upregulated in mouse LLC. Immunization with rAd‐FAP/hlivin α‐transduced DCs suppressed LLC volume and improved the survival of tumor‐bearing mice. Immunization with rAd‐FAP/hlivin α‐transduced DCs enhanced the cytotoxic effect of splenic lymphocytes on LLC tumor‐derived CAFs. Conclusion: Injection with rAd‐FAP/hlivin α‐transduced DCs promotes immune‐enhanced tumor microenvironment by decreasing CAFs and suppresses tumor growth in LLC mouse models. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) are an immature group of myeloid‐derived cells generated from myeloid cell precursors in the bone marrow. MDSCs appear almost exclusively in pathological conditions, such as tumor progression and various inflammatory diseases. The leading function of MDSCs is their immunosuppressive ability, which plays a crucial role in tumor progression and metastasis through their immunosuppressive effects. Since MDSCs have specific molecular features, and only a tiny amount exists in physiological conditions, MDSC‐targeted therapy has become a promising research direction for tumor treatment with minimal side effects. In this review, we briefly introduce the classification, generation and maturation process, and features of MDSCs, and detail their functions under various circumstances. The present review specifically demonstrates the environmental specificity of MDSCs, highlighting the differences between MDSCs from cancer and healthy individuals, as well as tumor‐infiltrating MDSCs and circulating MDSCs. Then, we further describe recent advances in MDSC‐targeted therapies. The existing and potential targeted drugs are divided into three categories, monoclonal antibodies, small‐molecular inhibitors, and peptides. Their targeting mechanisms and characteristics have been summarized respectively. We believe that a comprehensive in‐depth understanding of MDSC‐targeted therapy could provide more possibilities for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Panax ginseng is a common natural product, which is well‐known to have a wide range of pharmacological activities in cancer. Its metabolite, compound K (CK), has been reported to have anticancer activity. We aimed to systematically review the literature for evidence of anticancer effects of CK. We conducted a systematic search in eight databases. We included all in vitro and in vivo studies investigating the anticancer effects of CK with no restrictions. Quality assessment was applied by ToxRTool. Fifty‐four articles were included in our study. The purity of CK in our included studies was at least 95%. The in vitro studies reported that CK had a potential anticancer activity on several cell lines including human lung cancer cell lines (A549, PC‐9), nasopharyngeal carcinoma cell line (Hk‐1), liver cancer cell line (BEL 7402), and pediatric acute myeloid leukemia cell lines (Kasumi‐1, MV4‐11). The in vivo studies reported a significant decrease in tumor volume in mice treated with CK. CK is a potential supplementary treatment in cancer chemotherapies. The safety and further clinical trials of CK should be explored for future drug development. [ABSTRACT FROM AUTHOR]

This review aimed to identify preclinical and clinical studies examining the effects of rosmarinic acid (RA), carnosic acid (CaA), rosmanol (RO), carnosol (CA), and ursolic acid (UA) against allergic and immunologic disorders. Various online databases, including PubMed, Science Direct, EMBASE, Web of Sciences, Cochrane trials, and Scopus, were searched from inception until October 2022. Due to the suppression of the nuclear factor‐κB (NF‐κB) pathway, the main factor in allergic asthma, RA may be a promising candidate for the treatment of asthma. The other ingredients comprising CA and UA reduce the expression of interleukin (IL)‐4, IL‐5, and IL‐13 and improve airway inflammation. Rosemary's anti‐cancer effect is mediated by several mechanisms, including DNA fragmentation, apoptosis induction, inhibition of astrocyte‐upregulated gene‐1 expression, and obstruction of cell cycle progression in the G1 phase. The compounds, essentially found in Rosemary essential oil, prevent smooth muscle contraction through its calcium antagonistic effects, inhibiting acetylcholine (ACH), histamine, and norepinephrine stimulation. Additionally, CA exhibits a substantially greater interaction with the nicotinic ACH receptor than a family of medications that relax the smooth muscles, making it a potent antispasmodic treatment. The components have demonstrated therapeutic effects on the immune, allergy, and respiratory disorders. [ABSTRACT FROM AUTHOR]

Summary: Research on tumor‐associated neutrophils (TAN) currently surges because of the well‐documented strong clinical relevance of tumor‐infiltrating neutrophils. This relevance is illustrated by strong correlations between high frequencies of intratumoral neutrophils and poor outcome in the majority of human cancers. Recent high‐dimensional analysis of murine neutrophils provides evidence for unexpected plasticity of neutrophils in murine models of cancer and other inflammatory non‐malignant diseases. New analysis tools enable deeper insight into the process of neutrophil differentiation and maturation. These technological and scientific developments led to the description of an ever‐increasing number of distinct transcriptional states and associated phenotypes in murine models of disease and more recently also in humans. At present, functional validation of these different transcriptional states and potential phenotypes in cancer is lacking. Current functional concepts on neutrophils in cancer rely mainly on the myeloid‐derived suppressor cell (MDSC) concept and the dichotomous and simple N1–N2 paradigm. In this manuscript, we review the historic development of those concepts, critically evaluate these concepts against the background of our own work and provide suggestions for a refinement of current concepts in order to facilitate the transition of TAN research from experimental insight to clinical translation. [ABSTRACT FROM AUTHOR]

The pathologies and lethality of lung cancers are associated with smoking, lifestyle, and genomic factors. Several experimental mouse models of lung cancer, including those induced via intrapulmonary injection and intratracheal injection, have been reported for evaluating the pharmacological effect of drugs. However, these models are not sufficient for evaluating the efficacy of drugs during screening, as these direct injection models ignore the native processes of cancer progression in vivo, resulting in the inadequate pathological formation of lung cancer. In the present study, we developed a novel intranasal injection model of lung cancer simulating the native lung cancer pathology for anticancer drug screening. A mouse lung cancer cell line (Lewis lung carcinoma; LCC) was intranasally injected into mouse lungs, and injected cell number‐dependent cancer proliferation was apparent in both the left and right lungs. Human non‐small‐cell lung cancer (NCI‐H460) cells were also intranasally injected into nude mice and similarly showed injected cell number‐dependent cancer growth. For the pharmacological evaluation of cisplatin, two different treatment frequencies were tested four times per month and twice a month. The intranasal injection model confirmed that cisplatin suppressed lung cancer progression to a greater extent under the more frequent treatment condition. In conclusion, these results indicated that our intranasal injection model is a powerful tool for investigating lung cancer pathology and may aid in the development of new anti‐lung cancer agents. [ABSTRACT FROM AUTHOR]

Recent years have witnessed the rapid development of the biomimetic nanotechnology regarding the use of certain components (such as cell membranes, extracellular vesicles, proteins, etc.) derived from different cells to fabricate nanoparticles (NPs) for cancer treatment. These biomimetic NPs usually inherit certain abilities from their parental cells, such as long blood circulation, capacity to escape from mononuclear phagocytic system, active tumor‐targeting, and controlled drug release. Immunocytes play vital roles in different tumor progression stages, and can quickly and accurately react to tumor progression via specific targeting and immune surveillance. Therefore, increasing studies focus on constructing biomimetic NPs with components isolated from immunocytes. This review introduces four main types of immunocyte‐derived nanodrugs—membrane‐coated NPs, exosomes or extracellular vesicles, functional protein‐incorporated NPs, and exosome mimetics—and summarizes the recent advances of these nanodrugs for cancer therapy. Some current challenges and future research directions of immunocyte‐derived nanodrugs are also proposed. It is hoped that this review may help researchers in the related field to design new immunocyte‐derived nanomedicines and promote their preclinical and clinical applications in the near future. [ABSTRACT FROM AUTHOR]

The stimulator of interferon genes (STING) pathway is important for anticancer immune responses. However, the relative contributions of host and tumour STING in anti‐programmed cell death protein 1 (anti‐PD‐1) inhibitor responses in non‐small cell lung cancer (NSCLC) are unknown. STING expression in tumour and blood was associated with anti‐PD‐1 therapy in NSCLC patients; Moreover, loss of PD‐1 inhibitor therapeutic potency was demonstrated in STING KO (knock out) splenocytes and STING KO mice. STING knock‐down in tumour cells had no effect. STING on CD8+ T cells and host cells, not tumour cells, correlated with clinical effect of anti‐PD‐1 therapy in NSCLC patients. Finally, adoptive transfer of CD8+ T cells restored PD‐1 inhibitor anticancer effects. STING in host cells but not in tumour cells mediates anti‐PD‐1 inhibitor responses in cancer immunotherapy and could be used to select advantageous NSCLC patients from immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer cachexia is defined as a multi‐factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50–80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focusing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia and subsequently explores the available respiratory‐ and exercise‐focused literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise‐induced support of muscle via antioxidant and anti‐inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function and muscle glucose uptake provide avenues for interventional studies. Currently available pre‐clinical mouse models including novel transgenic animals provide a platform for the development of multi‐modal therapeutic strategies to protect respiratory muscles in people with cancer. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a multifactorial disease that causes continuous skeletal muscle wasting. Thereby, it seems to be a key determinant of cancer‐related death. Although anamorelin, a ghrelin receptor agonist, has been approved in Japan for the treatment of cachexia, few medical treatments for cancer cachexia are currently available. Myostatin (MSTN)/growth differentiation factor 8, which belongs to the transforming growth factor‐β family, is a negative regulator of skeletal muscle mass, and inhibition of MSTN signaling is expected to be a therapeutic target for muscle‐wasting diseases. Indeed, we have reported that peptide‐2, an MSTN‐inhibiting peptide from the MSTN prodomain, alleviates muscle wasting due to cancer cachexia. Herein, we evaluated the therapeutic benefit of myostatin inhibitory D‐peptide‐35 (MID‐35), whose stability and activity were more improved than those of peptide‐2 in cancer cachexia model mice. The biologic effects of MID‐35 were better than those of peptide‐2. Intramuscular administration of MID‐35 effectively alleviated skeletal muscle atrophy in cachexia model mice, and the combination therapy of MID‐35 with anamorelin increased food intake and maximized grip strength, resulting in longer survival. Our results suggest that this combination might be a novel therapeutic tool to suppress muscle wasting in cancer cachexia. [ABSTRACT FROM AUTHOR]

It is critical to discover novel biomarkers of lung cancer for establishing economical technology for diagnosis of lung cancer. Our study has suggested that the autofluorescence (AF) of the skin may become a novel biomarker of this type: First, development of lung cancer led to a significant increase in the skin's green AF in a mouse model of lung cancer; second, lung cancer patients had significantly higher skin's green AF at certain positions compared with healthy volunteers and pulmonary infection patients; and third, using the skin's green AF intensity at dorsal centremetacarpus as the variable, the areas under curve (AUC) for differentiating lung cancer patients and pulmonary infection patients and for differentiating lung cancer patients and healthy volunteers was 0.871 and 0.813, respectively. Collectively, our study has indicated that the skin's green AF at dorsal centremetacarpus may become a novel biomarker for establishing a ground‐breaking diagnostic strategy for lung cancer. [ABSTRACT FROM AUTHOR]

Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer‐induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor‐bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor‐bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer‐induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases. Synopsis: Cancer induces striking alterations in iron metabolism of the skeletal muscle and iron supplementation prevents muscle atrophy and loss of strength. Cancer‐induced muscle atrophy features suppressed TFR1 expression and impaired iron sensing.Reduction of iron availability by means of chemical chelators, iron‐deficient diet, or genetic knockdown of TFR1 in vitro and/or in vivo is sufficient to trigger muscle atrophy.Replenishing mitochondrial iron rescues cancer‐induced metabolic dysfunction.Iron supplementation prevents muscle wasting in tumor‐bearing mice and improves cancer patient strength. [ABSTRACT FROM AUTHOR]

Tumor metastasis is a series of complicated biological events. Hematogenous metastasis mediated by von Willebrand factor (vWF) is critical in tumor metastasis. However, the source of vWF and its role in tumor metastasis are controversial, and the further mechanism involved in mediating tumor metastasis is still unclear. In this study, we first demonstrated that lung adenocarcinoma cells could express vWF de novo and promotes tumor metastasis. Through the analysis of transcriptome sequencing, the metastasis promotion effect of vWF may be related to phosphorylase kinase subunit G1 (PHKG1), a catalytic subtype of phosphorylase kinase (PhK). PHKG1 was highly expressed in lung adenocarcinoma patients and led to poor prognosis. Further experiments found that lung adenocarcinoma–derived vWF induced the upregulation of PHKG1 through the PI3K/AKT pathway to promote glycogenolysis. Glycogen was funneled into glycolysis, leading to increased metastasis. Tumor metastasis assayed in vitro and in vivo showed that knockdown of PHKG1 or synergistic injection of phosphorylase inhibition based on the overexpression of vWF could inhibit metastasis. In summary, our research proved that lung adenocarcinoma–derived vWF may mediate tumor metastasis by regulating PHKG1 to promote glycogen metabolism and suggested potential targets for inhibition of lung adenocarcinoma metastasis. [ABSTRACT FROM AUTHOR]

Polysaccharides extracted from Asian traditional food source have been demonstrated to possess different antitumor activities mostly without side effect. In this paper, we reviewed many kinds of polysaccharides from different Asian food source and their antitumor activities. Some are common food such as different mushroom with more research. Some are special e.g., Ginseng,Salvia,Astragalus,Lycium barbarum etc. with relatively fewer research. This review mainly focused on their structure, derivatives, antitumor activities and their mechanism of action in the last decades. It aimed to bridge traditional Asian ingredients with tumor and cancer curation in order to avoid side effect of traditional treatment. Practical applications: There are abundant resources of Asian food. And polysaccharides from these resources have been showed good antitumor activities and immunopotentiating activity. This review introduced the advance of the polysaccharides and their antitumor activities, which will promote the development antitumor medicine derived from Asian food source, or their applications as Adjuvant therapy of traditional chemotherapy and radiotherapy. Due to their multiple antitumor activities, enhancing immunity potential, and non‐toxic side‐effects, it might be utilized for the treatment of multiple tumors and improve the health and the life quality of patients whether as anti‐tumor drugs or as adjuvant therapy method. Furthermore, traditional Asian food source is rich. In the near future, more and more efficient polysaccharides with antitumor activities of Asian food source will be discovered. There will be broad application market for the polysaccharides. [ABSTRACT FROM AUTHOR]

Multispectral analysis of coregistered multiparametric magnetic resonance (MR) images provides a powerful method for tissue phenotyping and segmentation. Acquisition of a sufficiently varied set of multicontrast MR images and parameter maps to objectively define multiple normal and pathologic tissue types can require long scan times. Accelerated MRI on clinical scanners with multichannel receivers exploits techniques such as parallel imaging, while accelerated preclinical MRI scanning must rely on alternate approaches. In this work, tumor‐bearing mice were imaged at 7 T to acquire k‐space data corresponding to a series of images with varying T1‐, T2‐ and T2*‐weighting. A joint reconstruction framework is proposed to reconstruct a series of T1‐weighted images and corresponding T1 maps simultaneously from undersampled Cartesian k‐space data. The ambiguity introduced by undersampling was resolved by using model‐based constraints and structural information from a reference fully sampled image as the joint total variation prior. This process was repeated to reconstruct T2‐weighted and T2*‐weighted images and corresponding maps of T2 and T2* from undersampled Cartesian k‐space data. Validation of the reconstructed images and parameter maps was carried out by computing tissue‐type maps, as well as maps of the proton density fat fraction (PDFF), proton density water fraction (PDwF), fat relaxation rate (R2f*) and water relaxation rate (R2w*) from the reconstructed data, and comparing them with ground truth (GT) equivalents. Tissue‐type maps computed using 18% k‐space data were visually similar to GT tissue‐type maps, with dice coefficients ranging from 0.43 to 0.73 for tumor, fluid adipose and muscle tissue types. The mean T1 and T2 values within each tissue type computed using only 18% k‐space data were within 8%–10% of the GT values from fully sampled data. The PDFF and PDwF maps computed using 27% k‐space data were within 3%–15% of GT values and showed good agreement with the expected values for the four tissue types. [ABSTRACT FROM AUTHOR]

Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis. [ABSTRACT FROM AUTHOR]

Metastasis is the main cause of death in individuals with cancer. Immune checkpoint blockade (ICB) can potentially reverse CD8+ cytotoxic T lymphocytes (CTLs) dysfunction, leading to significant remission in multiple cancers. However, the mechanism underlying the development of CTL exhaustion during metastatic progression remains unclear. Here, we established an experimental pulmonary metastasis model with melanoma cells and discovered a critical role for melanoma‐released exosomes in metastasis. Using genetic knockdown of nSMase2 and Rab27a, 2 key enzymes for exosome secretion, we showed that high levels of effector‐like tumor‐specific CD8+ T cells with transitory exhaustion, instead of terminal exhaustion, were observed in mice without exosomes; these cells showed limited inhibitory receptors and strong proliferation and cytotoxicity. Mechanistically, the immunosuppression of exosomes depends on exogenous PD‐L1, which can be largely rescued by pretreatment with antibody blockade. Notably, we also found that exosomal PD‐L1 acts as a promising predictive biomarker for ICB therapies during metastasis. Together, our findings suggest that exosomal PD‐L1 may be a potential immunotherapy target, suggesting a new curative therapy for tumor metastasis. [ABSTRACT FROM AUTHOR]

Nuclear receptors, liver X receptor‐α (LXRα; NR1H3) and liver X receptor‐β (LXRβ; NR1H2), are considered master regulators of lipid homeostasis. During the last couple of decades, their pivotal roles in several physiological and pathological processes ranging from energy supply, immunity, cardiovascular, neurodegenerative disorders and cancer have been highlighted. In this review, the main results achieved during more recent years about our understanding of the LXR involvement in cancer has been mainly obtained using small‐molecule chemical probes. Remarkably, all these probes, albeit having different structure and biological properties, have a well demonstrated anti‐tumoral activity arising from LXR modulation, indicating a high potential of LXR targeting for the treatment of cancer. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc [ABSTRACT FROM AUTHOR]

Anti‐angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early‐stage (resectable) cancers. Newer investigational anti‐angiogenic drugs have been designed to inhibit the Angiopoietin (Ang)‐Tie pathway. Acting through Tie2 receptors, the Ang1 ligand is a gatekeeper of endothelial quiescence. Ang2 is a dynamically expressed pro‐angiogenic destabilizer of endothelium, and its upregulation is associated with poor prognosis in cancer. Besides using Ang2 blockers as inhibitors of tumor angiogenesis, little attention has been paid to their use as stabilizers of blood vessels to suppress tumor cell extravasation and metastasis. In clinical trials, Ang2 blockers have shown limited efficacy in advanced metastatic disease settings. This review summarizes preclinical evidence suggesting the potential utility of Ang2 inhibitors or Tie2 activators as neoadjuvant or adjuvant therapies in the prevention or treatment of early‐stage micrometastatic disease. We further discuss the rationale and potential of combining these strategies with immunotherapy, including immune checkpoint targeting antibodies. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer‐related deaths worldwide, in which angiogenesis is highly required for lung cancer cell growth and metastasis. Genetic regulation of this multistep process is being studied extensively, however, relatively less is known about the epigenetic regulation of angiogenesis in lung cancer. Several epigenetic alterations contribute to regulating angiogenesis, such as epimodifications of DNA, posttranslational modification of histones, and expression of noncoding RNAs. Here, we review the current knowledge of the epigenetic regulation of angiogenesis and discuss the potential clinical applications of epigenetic‐based anticancer therapy in lung cancer. Overall, epigenetic‐based therapy will likely emerge as a prominent approach to treat lung cancer in the future. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is a vital component of therapeutically induced anti‐tumor immunity. An iridium(III) complex (Ir1), containing an N,N‐bis(2‐chloroethyl)‐azane derivate, as an endoplasmic reticulum‐localized ICD inducer for non‐small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage‐associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1‐treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long‐acting anti‐tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir‐based complex that is capable of developing an immunomodulatory response by immunogenic cell death. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is extremely complex, involving extensive interactions among stromal cells, immune cells, and signaling molecules. Therefore, an approach targeting the TME has emerged as a promising therapeutic strategy. Herbal medicines consist of multiple active compounds, which have multi‐target effects. Therefore, they have been regarded as potential anticancer agents; multiple studies have explored their effects on the TME. In this review, we report the effects of 29 single herb medicines or herbal formulas on the TME, based on the findings of 64 published studies. Specifically, we describe the effects of these herbal medicines on cancer‐associated fibroblasts/tumor‐associated fibroblasts, tumor‐associated endothelial cells, myeloid‐derived suppressor cells, and tumor‐associated macrophages. Among the reviewed herbal medicines, the most promising TME‐modulating effects were exhibited by curcumin, DHA, EGCG, resveratrol, and silibinin; these medicines showed the ability to regulate two or more components of the TME. The findings of this review support the notion that the combination of herbal medicines with conventional anticancer therapies are likely to exhibit a clinical benefit, which should be further explored in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer‐related deaths. Oxidative stress is a critical player in the induction and progression of age‐related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia. Methods: Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate‐buffered saline (saline) into the hind flank of female wild‐type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild‐type and Sod1KO saline and tumour‐bearing mice. Data were analysed by two‐way ANOVA with Tukey–Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM. Results: Muscle mass and cross‐sectional area were significantly reduced, in tumour‐bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour‐bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour‐bearing wild‐type mice (wild‐type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour‐bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour‐bearing mice compared with saline‐injected wild‐type mice. Mitochondrial protein degradation increased in tumour‐bearing wild‐type mice (wild‐type saline, 0.0204 ± 0.00159; wild‐type LLC, 0.167 ± 0.00157) and tumour‐bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour‐bearing wild‐type mice (wild‐type saline, 38.2 ± 0.861; wild‐type LLC, 28.8 ± 0.772). Three out of eleven of the tumour‐bearing Sod1KO mice did not survive the 3‐week period following tumour implantation. Conclusions: Oxidative stress does not exacerbate cancer‐induced muscle loss; however, cancer cachexia may accelerate NMJ disruption. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) promote tumor growth and metastasis, and are closely related with poor prognosis of cancers. Therefore, TAMs have been an attractive target in cancer therapy. This study investigated whether the root bark of Morus alba L. (MA) regulates TAMs. Methylene chloride extract of MA (MEMA) decreased the migration of RAW264.7 cells and THP‐1 macrophages toward cancer cells via inhibition of focal adhesion kinase and Src activity. In addition, MEMA inhibited the phorbol myristate acetate‐stimulated secretion of plasminogen activator inhibitor‐1 from cancer cells, leading to the decreased chemotaxis of macrophages. Finally, MEMA‐suppressed M2 macrophage polarization induced by interleukin (IL)‐4/IL‐13 or IL‐6. MEMA downregulated the mRNA expression of M2 macrophage markers and decreased the phosphorylation of signal transducer and activator of transcription (STAT) 6 and STAT3 in RAW264.7 cells. Suppression of M2 polarization of macrophages by MEMA resulted in the reduced migration of Lewis lung carcinoma cells when the conditioned media from RAW264.7 cells was used as a chemoattractant. Taken together, our results demonstrate that MEMA regulates TAMs by blocking the recruitment of macrophages into tumor microenvironments and by inhibiting M2 polarization of macrophages. [ABSTRACT FROM AUTHOR]

Background: The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis. Tumor‐associated macrophages (TAMs) are able to orchestrate tumor promoting and suppressing mechanisms in CRC. The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype‐specific metabolic pathways to identify potential new targets for CRC treatment. Methods: A literature search was performed using PubMed, Cochrane and Embase to identify studies on TAMs and their metabolism in CRC. The following search terms were used in various combinations: (obesity OR adiposity OR obese) AND (macrophage OR polarization OR macrophage metabolism) AND ((colon cancer*) OR (colon carcinoma) OR (colonic tumor*) OR (colonic neoplasm[MeSH]) OR (rectal cancer*) OR (rectal carcinoma) OR (rectal tumor*) OR (rectal neoplasm[MeSH]) OR (colorectal cancer*) OR (colorectal carcinoma) OR (colorectal tumor*) OR (colorectal neoplasm[MeSH])). Studies including data on the phenotype and metabolism of TAMs in CRC were analyzed. Results: Evidence for the prognostic utility of macrophage markers in CRC is currently evolving, with a particular role of stage‐dependent cellular metabolism profiles of TAMs. Itaconate is one of the metabolites produced by proinflammatory subtypes of TAMs and it is known to have tumor promoting effects. Metabolic pathways that are involved in macrophage activation and reprogramming play a role in a chronic inflammatory setting, consequently affecting the onset and development of CRC. Conclusions: Tumor‐promoting metabolites, such as itaconate, are directly regulating these mechanisms, thereby triggering carcinogenesis. Metabolic reprogramming in TAMs can build a bridge between metabolic dysfunction and the onset and progression of CRC through inflammatory pathways, particularly in younger patients with early‐onset CRC. [ABSTRACT FROM AUTHOR]