bims-stacyt 2022-01-16 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–01–16
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion.
Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy.
Tumor-Derived Extracellular Vesicles Induce Abnormal Angiogenesis via TRPV4 Downregulation and Subsequent Activation of YAP and VEGFR2.
TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation.
C/EBPβ promotes the expression of atrophy-inducing factors by tumours and is a central regulator of cancer cachexia.
Paracrine production of IL-6 promotes a hypercoagulable state in pancreatic cancer.
Directing hypoxic tumor microenvironment and HIF to illuminate cancer immunotherapy's existing prospects and challenges in drug targets.
Nanoenabled Tumor Oxygenation Strategies for Overcoming Hypoxia-Associated Immunosuppression.

Cancers (Basel). 2022 Jan 04. pii: 250. [Epub ahead of print]14(1):

Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion.

Sophiya Siddiqui, Rainer Glauben.

  The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression.

Keywords:  immunosuppression; lipid droplet (LD); metabolic reprogramming; myeloid derived suppressor cells (MDSCs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/cancers14010250
Molecules. 2021 Dec 27. pii: 137. [Epub ahead of print]27(1):

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy.

Zhi-Jian Han, Yang-Bing Li, Lu-Xi Yang, Hui-Juan Cheng, Xin Liu, Hao Chen.

  In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

Keywords:  CXC receptors 1 and 2; cancer-associated fibroblast; chemokine; immunotherapy; interleukin-8; microbiome; myeloid-derived suppressor cells; neutrophile; tumor microenvironment

DOI:  https://doi.org/10.3390/molecules27010137
Front Bioeng Biotechnol. 2021 ;9 790489

Tumor-Derived Extracellular Vesicles Induce Abnormal Angiogenesis via TRPV4 Downregulation and Subsequent Activation of YAP and VEGFR2.

Brianna Guarino, Venkatesh Katari, Ravi Adapala, Neha Bhavnani, Julie Dougherty, Mahmood Khan, Sailaja Paruchuri, Charles Thodeti.

  Tumor angiogenesis is initiated and maintained by the tumor microenvironment through secretion of autocrine and paracrine factors, including extracellular vesicles (EVs). Although tumor-derived EVs (t-EVs) have been implicated in tumor angiogenesis, growth and metastasis, most studies on t-EVs are focused on proangiogenic miRNAs and growth factors. We have recently demonstrated that conditioned media from human lung tumor cells (A549) downregulate TRPV4 channels and transform normal endothelial cells to a tumor endothelial cell-like phenotype and induce abnormal angiogenesis in vitro, via t-EVs. However, the underlying molecular mechanism of t-EVs on endothelial cell phenotypic transition and abnormal angiogenesis in vivo remains unknown. Here, we demonstrate that t-EVs downregulate TRPV4 expression post-translationally and induce abnormal angiogenesis by activating Rho/Rho kinase/YAP/VEGFR2 pathways. Further, we demonstrate that t-EVs induce abnormal vessel formation in subcutaneously implanted Matrigel plugs in vivo (independent of tumors), which are characterized by increased VEGFR2 expression and reduced pericyte coverage. Taken together, our findings demonstrate that t-EVs induce abnormal angiogenesis via TRPV4 downregulation-mediated activation of Rho/Rho kinase/YAP/VEGFR2 pathways and suggest t-EVs and TRPV4 as novel targets for vascular normalization and cancer therapy.

Keywords:  endothelial cells; extracellular vesicles; transient receptor potential vanilloid 4; tumor angiogenesis; vascular endothelial growth factor receptor 2

DOI:  https://doi.org/10.3389/fbioe.2021.790489
Cell Death Discov. 2022 Jan 10. 8(1): 3

TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation.

Fanglong Wu, Shimeng Wang, Qingxiang Zeng, Junjiang Liu, Jin Yang, Jingtian Mu, Hongdang Xu, Lanyan Wu, Qinghong Gao, Xin He, Ying Liu, Hongmei Zhou.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

DOI: https://doi.org/10.1038/s41420-021-00804-6
J Cachexia Sarcopenia Muscle. 2022 Jan 10.

C/EBPβ promotes the expression of atrophy-inducing factors by tumours and is a central regulator of cancer cachexia.

Hamood AlSudais, Rashida Rajgara, Aisha Saleh, Nadine Wiper-Bergeron.

   BACKGROUND: CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor whose high expression in human cancers is associated with tumour aggressiveness and poor outcomes. Most advanced cancer patients will develop cachexia, characterized by loss of skeletal muscle mass. In response to secreted factors from cachexia-inducing tumours, C/EBPβ is stimulated in muscle, leading to both myofibre atrophy and the inhibition of muscle regeneration. Involved in the regulation of immune responses, C/EBPβ induces the expression of many secreted factors, including cytokines. Because tumour-secreted factors drive cachexia and aggressive tumours have higher expression of C/EBPβ, we examined a potential role for C/EBPβ in the expression of tumour-derived cachexia-inducing factors.
METHODS: We used gain-of-function and loss-of-function approaches in vitro and in vivo to evaluate the role of tumour C/EBPβ expression on the secretion of cachexia-inducing factors.
RESULTS: We report that C/EBPβ overexpression up-regulates the expression of 260 secreted protein genes, resulting in a secretome that inhibits myogenic differentiation (-31%, P < 0.05) and myotube maturation [-38% (fusion index) and -25% (myotube diameter), P < 0.05]. We find that knockdown of C/EBPβ in cachexia-inducing Lewis lung carcinoma cells restores myogenic differentiation (+25%, P < 0.0001) and myotube diameter (+90%, P < 0.0001) in conditioned medium experiments and, in vivo, prevents muscle wasting (-51% for small myofibres vs. controls, P < 0.01; +140% for large myofibres, P < 0.01). Conversely, overexpression of C/EBPβ in non-cachectic tumours converts their secretome into a cachexia-inducing one, resulting in reduced myotube diameter (-41%, P < 0.0001, EL4 model) and inhibition of differentiation in culture (-26%, P < 0.01, EL4 model) and muscle wasting in vivo (+98% small fibres, P < 0.001; -76% large fibres, P < 0.001). Comparison of the differently expressed transcripts coding for secreted proteins in C/EBPβ-overexpressing myoblasts with the secretome from 27 different types of human cancers revealed ~18% similarity between C/EBPβ-regulated secreted proteins and those secreted by highly cachectic tumours (brain, pancreatic, and stomach cancers). At the protein level, we identified 16 novel secreted factors that are present in human cancer secretomes and are up-regulated by C/EBPβ. Of these, we tested the effect of three factors (SERPINF1, TNFRSF11B, and CD93) on myotubes and found that all had atrophic potential (-33 to -36% for myotube diameter, P < 0.01).
CONCLUSIONS: We find that C/EBPβ is necessary and sufficient to induce the secretion of cachexia-inducing factors by cancer cells and loss of C/EBPβ in tumours attenuates muscle atrophy in an animal model of cancer cachexia. Our findings establish C/EBPβ as a central regulator of cancer cachexia and an important therapeutic target.

Keywords:  CCAAT-enhancer-binding proteins; Cachexia; Carcinoma, Lewis lung; Muscle, skeletal; Muscular atrophy; Secreted proteins

DOI:  https://doi.org/10.1002/jcsm.12909
Am J Cancer Res. 2021 ;11(12): 5992-6003

Paracrine production of IL-6 promotes a hypercoagulable state in pancreatic cancer.

Silu Wang, Linyong Du, Hao Chen, Xing Zhang, Bicheng Chen, Lihong Yang.

Venous thromboembolism is the most common complication and the secondary cause of death in pancreatic cancer. Moreover, the hypercoagulable state induces microcirculation dysfunction, acidosis and hypoxia, and further enhances tumor immune evasion, tumor growth and metastasis. Numerous studies have revealed that patients with malignant tumors have high levels of IL-6, which stimulates hepatocytes to synthesize thrombopoietin, causing an increase in platelets. This study found that the concentration of IL-6 in pancreatic cancer patient sera was higher than that in healthy donors, while pancreatic cancer cells had low expression levels of IL-6, which was different from other types of cancer. This contradictory result prompted us to uncover the underlying mechanism. Our data revealed that pancreatic cancer enhanced IL-6 production in fibroblasts via the Jagged/Notch axis, while IL-6 further elevated Jagged-1/2 expression in a paracrine positive feedback loop in pancreatic cancer. Inhibition experiments and RNAi studies demonstrated that IL-6-induced Jagged-1/2 production in pancreatic cancer depended on STAT3 and that Jagged-1/2 enhanced IL-6 mRNA expression in HSFs through the NF-κB pathway. Finally, the animal study showed that knockdown of Jagged-1/2 or blockade of the Jagged/Notch pathway by Nirogacestat could alleviate pancreatic cancer-induced hypercoagulability. Accordingly, our findings clarified the key role of the Jagged/Notch/IL-6/STAT3 feedback loop in the development of a hypercoagulable state in pancreatic cancer, which also provides new therapeutic strategies for pancreatic cancer patients who suffer from hypercoagulability.

Keywords: IL-6; Pancreatic cancer; feedback loop; fibroblast; hypercoagulability; jagged/notch
Curr Drug Targets. 2022 Jan 11.

Directing hypoxic tumor microenvironment and HIF to illuminate cancer immunotherapy's existing prospects and challenges in drug targets.

Suman Kumar Ray, Sukhes Mukherjee.

  Cancer is now also reflected as a disease of the tumor microenvironment, primarily supposed to be a decontrolled genetic and cellular expression disease. Over the past two decades, significant and rapid progress has been made in recognizing the dynamics of the tumor's microenvironment and its contribution to influencing the response to various anti-cancer therapies and drugs. Modulations in the tumor microenvironment and immune checkpoint blockade are interesting in cancer immunotherapy and drug targets. Simultaneously, the immunotherapeutic strategy can be done by modulating the immune regulatory pathway; however, the tumor microenvironment plays an essential role in suppressing the antitumor's immunity by its substantial heterogeneity. Hypoxia inducible factor (HIF) is a significant contributor to solid tumor heterogeneity and a key stressor in the tumor microenvironment to drive adaptations to prevent immune surveillance. Checkpoint inhibitors here halt the ability of cancer cells to stop the immune system from activating, and in turn, amplify your body's immune system to help destroy cancer cells. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways and important drugs involved are Ipilimumab and Nivolumab, mainly along with other drugs in this group. Targeting the hypoxic tumor microenvironment may provide a novel immunotherapy strategy, break down traditional cancer therapy resistance, and build the framework for personalized precision medicine and cancer drug targets. We hope that this knowledge can provide insight into the therapeutic potential of targeting Hypoxia and help to develop novel combination approaches of cancer drugs to increase the effectiveness of existing cancer therapies, including immunotherapy.

Keywords:  HIF; Tumor microenvironment; checkpoint inhibitors; hypoxia; immune surveillance; immunotherapy; precision medicine

DOI:  https://doi.org/10.2174/1389450123666220111114649
ACS Appl Bio Mater. 2021 Jan 18. 4(1): 277-294

Nanoenabled Tumor Oxygenation Strategies for Overcoming Hypoxia-Associated Immunosuppression.

Chao Zhang, Qinglong Yan, Jiang Li, Ying Zhu, Yu Zhang.

  Cancer immunotherapy, which initiates or strengthens innate immune responses to attack cancer cells, has shown great promise in cancer treatment. However, low immune response impacted by immunosuppressive tumor microenvironment (TME) remains a key challenge, which has been found related to tumor hypoxia. Recently, nanomaterial systems are proving to be excellent platforms for tumor oxygenation, which can reverse hypoxia-associated immunosuppression, strengthen the systemic antitumor immune responses, and thus afford a striking abscopal effect to clear metastatic cancer cells. In this review, we would like to survey recent progress in utilizing nanomaterials for tumor oxygenation through approaches such as in situ O2 generation, O2 delivery, tumor vasculature normalization, and mitochondrial-respiration inhibition. Their effects on tumor hypoxia-associated immunosuppression are highlighted. We also discuss the ongoing challenges and how to further improve the clinical prospect of cancer immunotherapy.

Keywords:  cancer immunotherapy; hypoxia; immunosuppression; nanoparticles; tumor oxygenation

DOI:  https://doi.org/10.1021/acsabm.0c01328