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Lung cancer has become the leading cause of cancer‐related deaths, surpassing all other forms of cancer. Among lung cancers, non‐small cell lung cancer (NSCLC) accounts for approximately 85% of cases. The use of tobacco, genetic traits, and radiation exposure are amongst the major reasons of lung cancer. The ongoing research in the medical field has considered the efficacy of nanocarriers in targeting various cancer cells. Among several biomaterials, lipid‐based nanocarriers have gained special attention due to their excellent compatibility, improved targeting efficacy, and encapsulation ability of diverse therapeutic agents. Phospholipids are naturally occurring amphiphilic moieties found in all living creatures. The presence of phospholipids in biomembrane aids the permeability of phospholipid‐based drug carrier. It can also facilitate targeting of therapeutic agents to cancer microenvironment without degrading the encapsulated drug. Phospholipids can be employed to develop conjugated nanocarriers and vesicular nanoformulation that can result in prolonged circulatory half‐life and controlled release of drugs. Phospholipids are also suitable biomaterials to attach a ligand for tissue‐specific targeting. Recent researches have reported effective targeting of chemotherapeutic agents, genes, and vaccines through phospholipid‐based nanocarriers to lung cancer cells. This review focuses on the rationality and applications of phospholipid‐based nanocarriers in lung cancer therapy. [ABSTRACT FROM AUTHOR]

Liver cancer is a major global health concern, ranking among the top causes of cancer-related deaths worldwide. Despite advances in medical research, the prognosis for liver cancer remains poor, largely due to the inherent limitations of current therapies. Traditional treatments like surgery, radiation, and chemotherapy often fail to provide long-term remission and are associated with significant side effects. Immunotherapy has emerged as a promising avenue for cancer treatment, leveraging the body's immune system to target and destroy cancer cells. However, its application in liver cancer has been limited. One of the primary challenges is the liver's unique immune microenvironment, which can inhibit the effectiveness of immunotherapeutic agents. This immune microenvironment creates a barrier, leading to drug resistance and reducing the overall efficacy of treatment. Recent studies have focused on understanding the immunological landscape of liver cancer to develop strategies that can overcome these obstacles. By identifying the specific factors within the liver that contribute to immune suppression and drug resistance, researchers aim to enhance the effectiveness of immunotherapy. Prospective strategies include combining immunotherapy with other treatments, using targeted therapies to modulate the immune microenvironment, and developing new agents that can bypass or counteract the inhibitory mechanisms in the liver. These advancements hold promise for improving outcomes in liver cancer treatment. [ABSTRACT FROM AUTHOR]

AbstractIn recent years, mostly spanning the past decade, the concept of immunometabolism has ushered with a novel perspective on carcinogenesis, tumor progression, and tumor response to therapy. It has become clear that the metabolic state of immune cells plays a significant role in shaping their antitumor or protumor activities within the cancer microenvironment. Consequently, the examination of tumor metabolic heterogeneity, including an exploration of immunometabolism, proves indispensable for enhancing prognostic tools and advancing the quest for personalized treatments. Here we have delved into how metabolic reprogramming profoundly influences the acquisition and maintenance of functional states, spanning from effector and cytotoxic profiles to regulatory and immunosuppressive phenotypes in both innate and adaptive immunity. These alterations wield considerable influence over tumor evolution and affect the outcome of cancer. Furthermore, we explore some of the cellular signaling mechanisms that underpin the metabolic and phenotypic flexibility of immune cells in response to external stimuli. [ABSTRACT FROM AUTHOR]

Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation (WBI) allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2+/− and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context. [ABSTRACT FROM AUTHOR]

Abstract Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation (WBI) allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2 +/− and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context.

Deciphering breast cancer treatment resistance remains hindered by the lack of models that can successfully capture the four-dimensional dynamics of the tumor microenvironment. Here, we show that microextrusion bioprinting can reproducibly generate distinct cancer and stromal compartments integrating cells relevant to human pathology. Our findings unveil the functional maturation of this millimeter-sized model, showcasing the development of a hypoxic cancer core and an increased surface proliferation. Maturation was also driven by the presence of cancer-associated fibroblasts (CAF) that induced elevated microvascular-like structures complexity. Such modulation was concomitant to extracellular matrix remodeling, with high levels of collagen and matricellular proteins deposition by CAF, simultaneously increasing tumor stiffness and recapitulating breast cancer fibrotic development. Importantly, our bioprinted model faithfully reproduced response to treatment, further modulated by CAF. Notably, CAF played a protective role for cancer cells against radiotherapy, facilitating increased paracrine communications. This model holds promise as a platform to decipher interactions within the microenvironment and evaluate stroma-targeted drugs in a context relevant to human pathology.

Up-regulating programmed cell death ligand-1(PD-L1) expressed on tumor cells and tumor-infiltrating myeloid cells interacting with up-regulated programmed cell death-1 (PD-1) expressed on tumor-infiltrating lymphoid cells greatly hinder their tumor-inhibiting effect. It is necessary to explore the deep mechanism of this negative effect, so as to find the potential methods to improve the immunotherapy efficiency. In this study, we found that the PD-1 expression in lung cancer-infiltrating type II innate lymphoid cells (ILC2s) was highly up-regulated, which greatly restrained the activation and function of ILC2s. Furthermore, anti-PD-1 could restore the inhibition and effective cytokine secretion of ILC2s when co-cultured with tumor cells. In vivo studies proved that anti-PD-1 treatment promoted the activation of tumor-infiltrating ILC2s and inhibited the tumor growth of LLC-bearing nude mice. Our studies demonstrate a new PD-1/PD-L1 axis regulating mechanism on innate immune cells, which provide a useful direction to ILC2s-based immunotherapy to cancer diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Cancer tissues contain a wide variety of immune cells that play critical roles in suppressing or promoting tumor progression. Macrophages are one of the most predominant populations in the tumor microenvironment and are composed of two classes: infiltrating macrophages from the bone marrow and tissue-resident macrophages (TRMs). This review aimed to outline the function of TRMs in the tumor microenvironment, focusing on lung cancer. Review Although the functions of infiltrating macrophages and tumor-associated macrophages have been intensively analyzed, a comprehensive understanding of TRM function in cancer is relatively insufficient because it differs depending on the tissue and organ. Alveolar macrophages (AMs), one of the most important TRMs in the lungs, are replenished in situ, independent of hematopoietic stem cells in the bone marrow, and are abundant in lung cancer tissue. Recently, we reported that AMs support cancer cell proliferation and contribute to unfavorable outcomes. Conclusion In this review, we introduce the functions of AMs in lung cancer and their underlying molecular mechanisms. A thorough understanding of the functions of AMs in lung cancer will lead to improved treatment outcomes.

Cancer vasculogenesis is a pivotal focus of cancer research and treatment given its critical role in tumor development, metastasis, and the formation of vasculogenic microenvironments. Traditional approaches to investigating cancer vasculogenesis face significant challenges in accurately modeling intricate microenvironments. Recent advancements in three-dimensional (3D) bioprinting technology present promising solutions to these challenges. This review provides an overview of cancer vasculogenesis and underscores the importance of precise modeling. It juxtaposes traditional techniques with 3D bioprinting technologies, elucidating the advantages of the latter in developing cancer vasculogenesis models. Furthermore, it explores applications in pathological investigations, preclinical medication screening for personalized treatment and cancer diagnostics, and envisages future prospects for 3D bioprinted cancer vasculogenesis models. Despite notable advancements, current 3D bioprinting techniques for cancer vasculogenesis modeling have several limitations. Nonetheless, by overcoming these challenges and with technological advances, 3D bioprinting exhibits immense potential for revolutionizing the understanding of cancer vasculogenesis and augmenting treatment modalities. [ABSTRACT FROM AUTHOR]

Background: Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain. Methods: Cell invasion was assessed using a transwell-based assay, protein-protein interactions by an immunoprecipitation-Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography. Results: We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/ S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion. Conclusion: We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cell (MDSC)‐like adherent cells (MLACs) are a recently identified CD11b+F4/80− myeloid cell subset that can infiltrate tumors early in development and promote their growth. Because of these functions, MLACs play an important role in establishing an immunosuppressive tumor microenvironment (TME). However, the lack of MLAC‐specific markers has hampered further characterization of this cell type. This study identifies the gene signature of MLACs by analyzing RNA‐sequencing (RNA‐seq) and public single‐cell RNA‐seq data, revealing that MLACs are an independent cell population that are distinct from other intratumoral myeloid cells. After combining proteome analysis of membrane proteins with RNA‐seq data, H2‐Ab1 and CD11c are indicated as marker proteins that can support the isolation of MLAC subsets from CD11b+F4/80− myeloid cells by fluorescence‐activated cell sorting. The CD11b+F4/80−H2‐Ab1+ and CD11b+F4/80−CD11c+ MLAC subsets represent approximately half of the MLAC population that is isolated based on their adhesion properties and possess gene signatures and functional properties similar to those of the MLAC population. Additionally, membrane proteome analysis suggests that MLACs express highly heterogeneous surface proteins. This study facilitates an integrated understanding of heterogeneous intratumoral myeloid cells, as well as the molecular and cellular details of the development of an immunosuppressive TME. [ABSTRACT FROM AUTHOR]

Abstract Background The tumor microenvironment clearly influences cancer progressing properties but less is known about how individual cancer microenvironments potentially moderate cancer treatment effects. By cultivating and treating cancer cell lines in patient-derived scaffolds (PDS), the impact of specific characteristics of individual cancer microenvironments can be incorporated in human-like growth modelling and cancer drug treatment testing. Methods PDSs from 78 biobanked primary breast cancer samples with known patient outcomes, were prepared and repopulated with donor breast cancer cell lines, followed by treatment with 5-fluorouracil or doxorubicin after cellular adaption to the various microenvironments. Cancer cell responses to the treatments were monitored by RNA-analyses, highlighting changes in gene sets representative for crucial tumor biological processes such as proliferation, cancer stem cell features, differentiation and epithelial-to-mesenchymal transition. Results The chemotherapy treatments induced distinct gene expression patterns in adapted cancer cells with clusters of similar treatment responses depending on the patient-derived cancer microenvironment used as growth substrate. The doxorubicin treatment displayed a favorable gene signature among surviving cancer cells with low proliferation (MKI67) and pluripotency features (NANOG, POU5F1), in comparison to 5-fluorouracil showing low proliferation but increased pluripotency. Specific gene changes monitored post-treatment were also significantly correlated with clinical data, including histological grade (NANOG), lymph node metastasis (SLUG) and disease-free patient survival (CD44). Conclusions This laboratory-based treatment study using patient-derived scaffolds repopulated with cancer cell lines, clearly illustrates that the human cancer microenvironment influences chemotherapy responses. The differences in treatment responses defined by scaffold-cultures have potential prognostic and treatment predictive values.

Acid–base homeostasis is a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH− by cytosolic Fenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHi stable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+ exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.

Recently, a breakthrough immunotherapeutic strategy of chimeric antigen receptor (CAR) T-cells has been introduced to hematooncology. However, to apply this novel treatment in solid cancers, one must identify suitable molecular targets in the tumors of choice. CEACAM family proteins are involved in the progression of a range of malignancies, including pancreatic and breast cancers, and pose attractive targets for anticancer therapies. In this work, we used a new CEACAM-targeted 2A3 single-domain antibody-based chimeric antigen receptor T-cells to evaluate their antitumor properties in vitro and in animal models. Originally, 2A3 antibody was reported to target CEACAM6 molecule; however, our in vitro co-incubation experiments showed activation and high cytotoxicity of 2A3-CAR T-cells against CEACAM5 and/or CEACAM6 high human cell lines, suggesting cross-reactivity of this antibody. Moreover, 2A3-CAR T-cells tested in vivo in the BxPC-3 xenograft model demonstrated high efficacy against pancreatic cancer xenografts in both early and late intervention treatment regimens. Our results for the first time show an enhanced targeting toward CEACAM5 and CEACAM6 molecules by the new 2A3 sdAb-based CAR T-cells. The results strongly support the further development of 2A3-CAR T-cells as a potential treatment strategy against CEACAM5/6-overexpressing cancers. [ABSTRACT FROM AUTHOR]

Background: The tumor microenvironment clearly influences cancer progressing properties but less is known about how individual cancer microenvironments potentially moderate cancer treatment effects. By cultivating and treating cancer cell lines in patient-derived scaffolds (PDS), the impact of specific characteristics of individual cancer microenvironments can be incorporated in human-like growth modelling and cancer drug treatment testing. Methods: PDSs from 78 biobanked primary breast cancer samples with known patient outcomes, were prepared and repopulated with donor breast cancer cell lines, followed by treatment with 5-fluorouracil or doxorubicin after cellular adaption to the various microenvironments. Cancer cell responses to the treatments were monitored by RNA-analyses, highlighting changes in gene sets representative for crucial tumor biological processes such as proliferation, cancer stem cell features, differentiation and epithelial-to-mesenchymal transition. Results: The chemotherapy treatments induced distinct gene expression patterns in adapted cancer cells with clusters of similar treatment responses depending on the patient-derived cancer microenvironment used as growth substrate. The doxorubicin treatment displayed a favorable gene signature among surviving cancer cells with low proliferation (MKI67) and pluripotency features (NANOG, POU5F1), in comparison to 5-fluorouracil showing low proliferation but increased pluripotency. Specific gene changes monitored post-treatment were also significantly correlated with clinical data, including histological grade (NANOG), lymph node metastasis (SLUG) and disease-free patient survival (CD44). Conclusions: This laboratory-based treatment study using patient-derived scaffolds repopulated with cancer cell lines, clearly illustrates that the human cancer microenvironment influences chemotherapy responses. The differences in treatment responses defined by scaffold-cultures have potential prognostic and treatment predictive values. [ABSTRACT FROM AUTHOR]

Cancer treatment development is a complex process, with tumor heterogeneity and inter-patient variations limiting the success of therapeutic intervention. Traditional two-dimensional cell culture has been used to study cancer metabolism, but it fails to capture physiologically relevant cell-cell and cell-environment interactions required to mimic tumor-specific architecture. Over the past three decades, research efforts in the field of 3D cancer model fabrication using tissue engineering have addressed this unmet need. The self-organized and scaffold-based model has shown potential to study the cancer microenvironment and eventually bridge the gap between 2D cell culture and animal models. Recently, three-dimensional (3D) bioprinting has emerged as an exciting and novel biofabrication strategy aimed at developing a 3D compartmentalized hierarchical organization with the precise positioning of biomolecules, including living cells. In this review, we discuss the advancements in 3D culture techniques for the fabrication of cancer models, as well as their benefits and limitations. We also highlight future directions associated with technological advances, detailed applicative research, patient compliance, and regulatory challenges to achieve a successful bed-to-bench transition.

Mammals exhibit large differences in rates of cancer malignancy, even though the tumor formation rates may be similar. In placental mammals, rates of malignancy correlate with the extent of placental invasion. Our Evolved Levels of Invasibility (ELI) framework links these two phenomena identifying genes that potentially confer resistance in stromal fibroblasts to limit invasion, from trophoblasts in the endometrium, and from disseminating melanoma in the skin. Herein, using patient data from The Cancer Genome Atlas (TCGA), we report that these anti-invasive genes may be crucial in melanoma progression in human patients, and that their loss is correlated with increased cancer spread and lowered survival. Our results suggest that, surprisingly, these anti-invasive genes, which have lower expression in humans compared to species with non-invasive placentation, may potentially prevent stromal invasion, while a further reduction in their levels increases the malignancy and lethality of melanoma. Our work links evolution, comparative biology, and cancer progression across tissues, indicating new avenues for using evolutionary medicine to prognosticate and treat human cancers.

Cancer vasculogenesis is a pivotal focus of cancer research and treatment given its critical role in tumor development, metastasis, and the formation of vasculogenic microenvironments. Traditional approaches to investigating cancer vasculogenesis face significant challenges in accurately modeling intricate microenvironments. Recent advancements in three-dimensional (3D) bioprinting technology present promising solutions to these challenges. This review provides an overview of cancer vasculogenesis and underscores the importance of precise modeling. It juxtaposes traditional techniques with 3D bioprinting technologies, elucidating the advantages of the latter in developing cancer vasculogenesis models. Furthermore, it explores applications in pathological investigations, preclinical medication screening for personalized treatment and cancer diagnostics, and envisages future prospects for 3D bioprinted cancer vasculogenesis models. Despite notable advancements, current 3D bioprinting techniques for cancer vasculogenesis modeling have several limitations. Nonetheless, by overcoming these challenges and with technological advances, 3D bioprinting exhibits immense potential for revolutionizing the understanding of cancer vasculogenesis and augmenting treatment modalities.

A systematic review protocol acts as a guide in the review process to prevent the introduction of bias, maintain transparency and allows reproducibility. Yoga intervention had been experimented on various health aspects such as physical functioning, health-related quality of life, psychosocial and emotional well-being among breast cancer populations, and the findings have been very encouraging. Studies are being performed on the effect of yoga intervention(s) at the molecular level by assessing the inflammatory cytokines and also stress hormones such as cortisol. This protocol is developed to escort in evaluating studies that have been performed on evidence-based yoga intervention at the level of cancer microenvironment, in women diagnosed with breast cancer, by assessing the inflammatory biomarkers and cortisol level, a primary stress marker, and a potent influence of inflammation. The findings will elucidate the picture of the cancer microenvironment as a result of yoga intervention. [ABSTRACT FROM AUTHOR]

Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is inevitable. Moreover, the biology of recurrent glioblastoma remains unclear. Increasing evidence has shown that intratumoral heterogeneity and the tumor microenvironment contribute to therapeutic resistance. However, the interaction between intracellular heterogeneity and drug resistance in recurrent GBMs remains controversial. The aim of this study was to map the transcriptome landscape of cancer cells and the tumor heterogeneity and tumor microenvironment in recurrent and drug‐resistant GBMs at a single‐cell resolution and further explore the mechanism of drug resistance of GBMs. We analyzed six tumor tissue samples from three patients with primary GBM and three patients with recurrent GBM in which recurrence and drug resistance developed after treatment with the standard Stupp protocol using single‐cell RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation of the expression of stemness‐related and cell‐cycle‐related genes was observed in recurrent GBM cells. Compared with the initial GBM tissues, recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports. Finally, vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results delineate the single‐cell map of recurrent glioblastoma, tumor heterogeneity, tumor microenvironment, and drug‐resistance mechanisms, providing new insights into treatment strategies for recurrent glioblastomas. [ABSTRACT FROM AUTHOR]

Abstract Background Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. Methods The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. Results Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. Conclusions Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM.

Abstract Intercellular communication plays an important role in cancer initiation and progression through direct contact and indirect interactions, such as via secretory molecules. Cancer-associated fibroblasts (CAFs) are one of the principal components of such communication with cancer cells, modulating cancer metastasis and tumour mechanics and influencing angiogenesis, the immune system, and therapeutic resistance. Over the past few years, there has been a significant increase in research on extracellular vesicles (EVs) as regulatory agents in intercellular communication. EVs enable the transfer of functional molecules, including proteins, mRNAs and microRNAs (miRNAs), to recipient cells. Cancer cells utilize EVs to dictate the specific characteristics of CAFs within the tumour microenvironment, thereby promoting cancer progression. In response to such “education” by cancer cells, CAFs contribute to cancer progression via EVs. In this review, we summarize experimental data indicating the pivotal roles of EVs in intercellular communication between cancer cells and CAFs.

The importance of the microenvironment is widely recognized as it regulates not only malignant cell behavior but also drug sensitivity. The cancer cell microenvironment is composed of biological, physical and chemical elements, and simultaneous reproduction of these three elements are important conditions investigated in cancer research. In the present study, we focused on the epidemiological and anatomical specificities of endometrioid carcinoma, obesity (biological), fluid flow (physical) and anticancer agents (chemical) to target the specific microenvironmental elements of endometrioid carcinoma. To elucidate the individual effects of these elements on endometrioid carcinoma and to investigate the relationships between these factors, we developed an adipose tissue fragments (ATFs)-embedded cell disc under a rotational culture method to generate carcinoma-stroma interactions and to create fluid flow. ATFs and fluid flow individually or synergistically influenced proliferative cellular behavior and the morphological changes underlying endometrioid carcinoma. ATFs and fluid flow also governed the expression of extracellular signal-regulated kinase and p38 signaling synergistically or individually, depending on the endometrioid carcinoma cell type. Adipose tissue induced chemoresistance to cis-diamminedichloro-platinum (CDDP) in endometrioid cancer, but the resistance effect was abolished by fluid flow. Thus, a simple reconstructed model was established to investigate three elements of the microenvironment of endometrioid carcinoma in vitro. This culture model unequivocally demonstrated the individual and synergistic effects of the three elements on endometrioid carcinoma. This new culture model is a promising tool for elucidating the mechanisms underlying endometrioid carcinoma and for developing further treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials. Methods: The effect of ruxolitinib on primary human CLL cells was studied in vitro and in vivo. Results: Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells in vitro. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited TLR-mediated IL10 transcription and markedly reduced IL-10 production in vitro. It also decreased blood levels of IL-10 while increasing TNFa along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells in vivo. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production in vitro but, in contrast to ruxolitinib, blocked initial IL10 transcription induced by TLR-signaling in vitro, decreased TNFa production, and deactivates CLL cells in vivo. Discussion: These findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NFkB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL. [ABSTRACT FROM AUTHOR]

Background: LOX familymembers are reported to play pivotal roles in cancer. Unlike their enzymatic activities in collagen cross-linking, their precise cancer functions are unclear. We revealed that LOXL4 is highly upregulated in breast cancer cells, and we thus sought to define an unidentified role of LOXL4 in breast cancer. Methods: We established theMDA-MB-231 sublines MDA-MB-231-LOXL4 mutCA and -LOXL4 KO, which stably overexpress mutant LOXL4 that loses its catalytic activity and genetically ablates the intrinsic LOXL4 gene, respectively. In vitro and in vivo evaluations of these cells' activities of cancer outgrowth were conducted by cell-based assays in cultures and an orthotopic xenograft model, respectively. The new target (s) of LOXL4 were explored by the MS/MS analytic approach. Results: Our in vitro results revealed that both the overexpression of mutCA and the KO of LOXL4 in cells resulted in a marked reduction of cell growth and invasion. Interestingly, the lowered cellular activities observed in the engineered cells were also reflected in the mouse model. We identified a novel binding partner of LOXL4, i.e., annexin A2. LOXL4 catalyzes cell surface annexin A2 to achieve a cross-linked multimerization of annexin A2, which in turn prevents the internalization of integrin β-1, resulting in the locking of integrin β-1 on the cell surface. These events enhance the promotion of cancer cell outgrowth. Conclusions: LOXL4 has a new role in breast cancer progression that occurs via an interaction with annexin A2 and integrin β-1 on the cell surface. [ABSTRACT FROM AUTHOR]

Metabolic obstacles of the tumor microenvironment remain a challenge to T-cell-mediated cancer immunotherapies. To better understand the interplay of immune checkpoint signaling and immune metabolism, this study developed and used an optimized metabolite extraction protocol for non-adherent primary human T-cells, to broadly profile in vitro metabolic changes effected by PD-1 signaling by mass spectrometry-based metabolomics and isotopomer analysis. Inhibitory signaling reduced aerobic glycolysis and glutaminolysis. A general scarcity across the panel of metabolites measured supported widespread metabolic regulation by PD-1. Glucose carbon fate analysis supported tricarboxylic acid cycle reliance on pyruvate carboxylation, catabolic-state fluxes into acetyl-CoA and succinyl-CoA, and a block in de novo nucleoside phosphate synthesis that was accompanied by reduced mTORC1 signaling. Nonetheless, exogenous administration of nucleosides was not sufficient to ameliorate proliferation of T-cells in the context of multiple metabolic insufficiencies due to PD-L1 treatment. Carbon fate analysis did not support the use of primarily glucose-derived carbons to fuel fatty acid beta oxidation, in contrast to reports on T-memory cells. These findings add to our understanding of metabolic dysregulation by PD-1 signaling and inform the effort to rationally develop metabolic interventions coupled with immune-checkpoint blockade for increased treatment efficacy.

IntroductionChronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials.MethodsThe effect of ruxolitinib on primary human CLL cells was studied in vitro and in vivo.ResultsRuxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells in vitro. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited TLR-mediated IL10 transcription and markedly reduced IL-10 production in vitro. It also decreased blood levels of IL-10 while increasing TNFα along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells in vivo. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production in vitro but, in contrast to ruxolitinib, blocked initial IL10 transcription induced by TLR-signaling in vitro, decreased TNFα production, and deactivates CLL cells in vivo.DiscussionThese findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NFκB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL.

The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and mortality of this disease can be traced back to a number of causes, including treatment-related side effects, drug resistance, inadequate curative treatment and tumor relapse. Recently, anti-cancer bioactive peptides (ACPs) have emerged as a potential therapeutic choice within the pharmaceutical arsenal due to their high penetration, specificity and fewer side effects. In this contribution, we present a general overview of the literature concerning the conformational structures, modes of action and membrane interaction mechanisms of ACPs, as well as provide recent examples of their successful employment as targeting ligands in cancer treatment. The use of ACPs as a diagnostic tool is summarized, and their advantages in these applications are highlighted. This review expounds on the main approaches for peptide synthesis along with their reconstruction and modification needed to enhance their therapeutic effect. Computational approaches that could predict therapeutic efficacy and suggest ACP candidates for experimental studies are discussed. Future research prospects in this rapidly expanding area are also offered. [ABSTRACT FROM AUTHOR]

The fundamental mechanism responsible for the aggressiveness of metastatic cancers such as triple-negative breast cancer (TNBC) is the epithelial-mesenchymal transition (EMT). In cancer microenvironments, the Phosphoinositide 3-kinases (PI3K)-Akt- mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating the EMT mechanism. The current study focuses on the impacts of rapamycin, a newly retargeted chemotherapeutic agent against mTOR, and MicroRNA (miR)-122 on the aggressive behavior of TNBC. The half-maximal inhibitory concentration (IC50) of rapamycin on 4T1 cells was determined using an MTT assay. Also, miR-122 was transiently transfected into 4T1 cells to study its effect on the pathway. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to assess the expression level of central mTOR and EMT-related cascade genes. Moreover, cell mobility and migration were evaluated using scratch and migration assays, respectively. Both rapamycin and miR-122 significantly decreased the expression levels of PI3K, AKT, and mTOR, as well as ZeB1 and Snail genes. However, no significant change was observed in Twist gene expression. Furthermore, scratch and migration assays revealed that the migration of 4T1 cells was markedly reduced, especially following miR-122 induction. Our experimental findings and gene enrichment studies indicated that miR-122 mainly operates on multiple metabolic pathways, as well as EMT and mTOR, while rapamycin has restricted targets in cancer cells, Consequently, miR-122 can be considered a potential cancer microRNA therapy option, which can be validated in the future in animal studies to demonstrate its efficacy in cancer control. [ABSTRACT FROM AUTHOR]

One of the important mechanisms in cancer cell metastasis is the cellular function of a specific cell type called myofibroblast cells. Myofibroblast cells are unique cell types that play an important role in the cancer cell microenvironment. As a step toward integrating the latest peer-reviewed cancer research findings into a general biology remote learning setting, we developed an innovative guest speaker talk to engage first-year undergraduates to develop a prediction on tumor microenvironment. In our article, we describe integrated remote approaches using Jamboard and reflective mentoring to validate and reflect on undergraduate team responses within an inclusive and equitable framework. These teaching and mentoring strategies provide a framework for senior undergraduates to be transformative role model scholars that inspire the next generation of Latinx and Native American undergraduates in important topics related to health and environment and the process of science for general biology undergraduates. [ABSTRACT FROM AUTHOR]

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia–niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells. [ABSTRACT FROM AUTHOR]

Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via "aerobic glycolysis" were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. Methods: The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. Results: Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. Conclusions: Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM. [ABSTRACT FROM AUTHOR]

The dense cancer microenvironment is a significant barrier that limits the penetration of anticancer agents, thereby restraining the efficacy of molecular and nanoscale cancer therapeutics. Developing new strategies to enhance the permeability of cancer tissues is of major interest to overcome treatment resistance. Nonetheless, early strategies based on small molecule inhibitors or matrix-degrading enzymes have led to disappointing clinical outcomes by causing increased chemotherapy toxicity and promoting disease progression. In recent years, photodynamic therapy (PDT) has emerged as a novel approach to increase the permeability of cancer tissues. By producing excessive amounts of reactive oxygen species selectively in the cancer microenvironment, PDT increases the accumulation, penetration depth, and efficacy of chemotherapeutics. Importantly, the increased cancer permeability has not been associated to increased metastasis formation. In this review, we provide novel insights into the mechanisms by which this effect, called photodynamic priming, can increase cancer permeability without promoting cell migration and dissemination. This review demonstrates that PDT oxidizes and degrades extracellular matrix proteins, reduces the capacity of cancer cells to adhere to the altered matrix, and interferes with mechanotransduction pathways that promote cancer cell migration and differentiation. Significant knowledge gaps are identified regarding the involvement of critical signaling pathways, and to which extent these events are influenced by the complicated PDT dosimetry. Addressing these knowledge gaps will be vital to further develop PDT as an adjuvant approach to improve cancer permeability, demonstrate the safety and efficacy of this priming approach, and render more cancer patients eligible to receive life-extending treatments. [ABSTRACT FROM AUTHOR]

The high mortality rate of colorectal cancer (CRC) highlights the need for new treatment strategies; however, the venous invasion mechanisms in tumor endothelial cells within CRC remain unexplored. Therefore, we investigated the clinicopathological features of SRY-box transcription factor 17 (SOX17) in CRC. Immunohistochemical staining was performed on 55 CRC tissue specimens using a SOX17-specific antibody, followed by Kaplan–Meier and Cox proportional hazards regression analyses. SOX17 immunoreactivity was detected in the endothelial cells of tumor-penetrating vessels in 35/55 CRC samples. Kaplan–Meier analysis indicated that patients with SOX17 immunoreactivity had favorable overall and progression-free survival (log-rank test, P = 0.03 and 0.02, respectively). Notably, tumor endothelial SOX17 immunoreactivity was associated with a favorable prognosis in patients with stage III or IV disease (OS, P = 0.0089; PFS, P = 0.0065). Cox proportional hazard regression analysis indicated that SOX17 immunoreactivity is an independent factor for predicting favorable overall and progression-free survival in CRC (P = 0.02 and 0.01, respectively). The present findings suggest that SOX17 expression in tumor endothelial cells is a potential indicator of favorable prognosis in patients with CRC. [ABSTRACT FROM AUTHOR]

The fundamental mechanism responsible for the aggressiveness of metastatic cancers such as triple-negative breast cancer (TNBC) is the epithelial-mesenchymal transition (EMT). In cancer microenvironments, the Phosphoinositide 3-kinases (PI3K)-Akt- mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating the EMT mechanism. The current study focuses on the impacts of rapamycin, a newly retargeted chemotherapeutic agent against mTOR, and MicroRNA (miR)-122 on the aggressive behavior of TNBC. The half-maximal inhibitory concentration (IC50) of rapamycin on 4T1 cells was determined using an MTT assay. Also, miR-122 was transiently transfected into 4T1 cells to study its effect on the pathway. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to assess the expression level of central mTOR and EMT-related cascade genes. Moreover, cell mobility and migration were evaluated using scratch and migration assays, respectively. Both rapamycin and miR-122 significantly decreased the expression levels of PI3K, AKT, and mTOR, as well as ZeB1 and Snail genes. However, no significant change was observed in Twist gene expression. Furthermore, scratch and migration assays revealed that the migration of 4T1 cells was markedly reduced, especially following miR-122 induction. Our experimental findings and gene enrichment studies indicated that miR-122 mainly operates on multiple metabolic pathways, as well as EMT and mTOR, while rapamycin has restricted targets in cancer cells. Consequently, miR-122 can be considered a potential cancer microRNA therapy option, which can be validated in the future in animal studies to demonstrate its efficacy in cancer control.

The most recent international guidelines regarding recurrent pregnancy loss (RPL) exclude most of the immunological tests recommended for RPL since they do not reach an evidence-based level. Comparisons for metanalysis and systematic reviews are limited by the ambiguity in terms of RPL definition, etiological and risk factors, diagnostic work-up, and treatments applied. Therefore, cohort heterogeneity, the inadequacy of numerosity, and the quality of data confirm a not standardized research quality in the RPL field, especially for immunological background, for which potential research application remains confined in a separate single biological layer. Innovative sequencing technologies and databases have proved to play a significant role in the exploration and validation of cancer research in the context of dataset quality and bioinformatics tools. In this article, we will investigate how bioinformatics tools born for large-scale cancer immunological research could revolutionize RPL immunological research but are limited by the nature of current RPL datasets.

In this report, we describe in detail the evolving procedures to optimize humanized mouse cohort generation, including optimal conditioning, choice of lineage for engraftment, threshold for successful engraftment, HNSCC tumor implantation, and immune and stroma cell analyses. We developed a dual infusion protocol of human hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem cells (MSCs), leading to incremental human bone marrow engraftment, and exponential increase in mature peripheral human immune cells, and intratumor homing that includes a more complete lineage reconstitution. Additionally, we have identified practical rules to predict successful HSPC/MSC expansion, and a peripheral human cell threshold associated with bone marrow engraftment, both of which will optimize cohort generation and management. The tremendous advances in immune therapy in cancer have made the need for appropriate and standardized models more acute than ever, and therefore, we anticipate that this manuscript will have an immediate impact in cancer-related research. The need for more representative tools to investigate the human tumor microenvironment (TME) has led to the development of humanized mouse models. However, the difficulty of immune system engraftment and minimal human immune cell infiltration into implanted xenografts are major challenges. We have developed an improved method for generating mismatched humanized mice (mHM), using a dual infusion of human HSPCs and MSCs, isolated from cord blood and expanded in vitro. Engraftment with both HSPCs and MSCs produces mice with almost twice the percentage of human immune cells in their bone marrow, compared to mice engrafted with HSPCs alone, and yields 9- to 38-fold higher levels of mature peripheral human immune cells. We identified a peripheral mHM blood human B cell threshold that predicts an optimal degree of mouse bone marrow humanization. When head and neck squamous cell carcinoma (HNSCC) tumors are implanted on the flanks of HSPC-MSC engrafted mice, human T cells, B cells, and macrophages infiltrate the stroma of these tumors at 2- to 8-fold higher ratios. In dually HSPC-MSC engrafted mice we also more frequently observed additional types of immune cells, including regulatory T cells, cytotoxic T cells, and MDSCs. Higher humanization was associated with in vivo response to immune-directed therapy. The complex immune environment arising in tumors from dually HSPC-MSC engrafted mice better resembles that of the originating patients tumor, suggesting an enhanced capability to accurately recapitulate a human TME.

G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted for cancer treatment, except for certain endocrine and hormone-responsive tumors. Limited knowledge regarding GPCR expression in cancer cells likely has contributed to this lack of use of GPCR-targeted drugs as cancer therapeutics. We thus undertook GPCRomic studies to define the expression of endoGPCRs (which respond to endogenous molecules such as hormones, neurotransmitters and metabolites) in multiple types of cancer cells. Using TaqMan qPCR arrays to quantify the mRNA expression of ∼340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal cells associated with CLL, breast cancer cell lines, colon cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, cancer associated fibroblasts (CAFs), and PDAC tumors express 50 to >100 GPCRs, including many orphan GPCRs (which lack known physiologic agonists). Limited prior data exist regarding the expression or function of most of the highly expressed GPCRs in these cancer cells and tumors. Independent results from public cancer gene expression databases confirm the expression of such GPCRs. We propose that highly expressed GPCRs in cancer cells (for example, GPRC5A in PDAC and colon cancer cells and GPR68 in PDAC CAFs) may contribute to the malignant phenotype, serve as biomarkers and/or may be novel therapeutic targets for the treatment of cancer.

Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via “aerobic glycolysis” were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.

Intercellular communication plays an important role in cancer initiation and progression through direct contact and indirect interactions, such as via secretory molecules. Cancer-associated fibroblasts (CAFs) are one of the principal components of such communication with cancer cells, modulating cancer metastasis and tumour mechanics and influencing angiogenesis, the immune system, and therapeutic resistance. Over the past few years, there has been a significant increase in research on extracellular vesicles (EVs) as regulatory agents in intercellular communication. EVs enable the transfer of functional molecules, including proteins, mRNAs and microRNAs (miRNAs), to recipient cells. Cancer cells utilize EVs to dictate the specific characteristics of CAFs within the tumour microenvironment, thereby promoting cancer progression. In response to such “education” by cancer cells, CAFs contribute to cancer progression via EVs. In this review, we summarize experimental data indicating the pivotal roles of EVs in intercellular communication between cancer cells and CAFs. [ABSTRACT FROM AUTHOR]

CAR-T cell therapies have been recognized as one of the most advanced and efficient strategies to treat patients with hematologic malignancies. However, similar results have not been observed for the treatment of solid tumors. One of the explanations is the fact that tumors have extremely hostile microenvironments for the infiltration and effector activity of T-cells, mainly due to the presence of highly suppressive cytokines, hypoxia, and reactive oxygen species. Taking advantage of cytokines functionally, new fourthgeneration CAR constructs have been developed to target tumor cells and additionally release cytokines that can contribute to the cytotoxicity of T-cells. The manufacturing process, including the use of cytokines in the expansion and differentiation of T cells, is also discussed. Finally, the clinical aspects and the influence of cytokines on the clinical condition of patients, such as cytokine release syndrome, who receive treatment with CAR-T cells are addressed. Therefore, this review aims to highlight how important cytokines are as one of the major players of cell therapy. [ABSTRACT FROM AUTHOR]

In recent years, mostly spanning the past decade, the concept of immunometabolism has ushered with a novel perspective on carcinogenesis, tumor progression, and tumor response to therapy. It has become clear that the metabolic state of immune cells plays a significant role in shaping their antitumor or protumor activities within the cancer microenvironment. Consequently, the examination of tumor metabolic heterogeneity, including an exploration of immunometabolism, proves indispensable for enhancing prognostic tools and advancing the quest for personalized treatments. Here we have delved into how metabolic reprogramming profoundly influences the acquisition and maintenance of functional states, spanning from effector and cytotoxic profiles to regulatory and immunosuppressive phenotypes in both innate and adaptive immunity. These alterations wield considerable influence over tumor evolution and affect the outcome of cancer. Furthermore, we explore some of the cellular signaling mechanisms that underpin the metabolic and phenotypic flexibility of immune cells in response to external stimuli.