bims-stacyt 2023-06-04 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–06–04
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Growth differentiation factor 15 induces cisplatin resistance through upregulation of xCT expression and glutathione synthesis in gastric cancer.
Exosomal B7-H3 facilitates colorectal cancer angiogenesis and metastasis through AKT1/mTOR/VEGFA pathway.
Update on Adipose Tissue and Cancer.
Lipid metabolism and tumor immunotherapy.
Obesity contributes to hepatocellular carcinoma development via immunosuppressive microenvironment remodeling.
Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance.
Metformin promotes angiogenesis by enhancing VEGFa secretion by adipose-derived stem cells via the autophagy pathway.

Cancer Sci. 2023 Jun 01.

Growth differentiation factor 15 induces cisplatin resistance through upregulation of xCT expression and glutathione synthesis in gastric cancer.

Sheng-Fan Wang, Yuh-Lih Chang, Wen-Liang Fang, Anna Fen-Yau Li, Chian-Feng Chen, Tien-Shun Yeh, Giun-Yi Hung, Kuo-Hung Huang, Hsin-Chen Lee.

  Gastric cancer is a common cancer worldwide, particularly in East Asia. Chemotherapy is used in adjuvant or palliative therapies for gastric cancer. However, subsequent chemoresistance often develops. Growth differentiation factor 15 (GDF15) links to several cancers, but its effect on chemoresistance in gastric cancer remains unclear. Here, we analyzed clinical samples from genetic databases and included patients with gastric cancer. We dissected the regulatory mechanism underlying GDF15-mediated resistance of cisplatin in human gastric cancer cells. We showed that GDF15 serum levels might be a valuable biomarker for predicting prognosis in gastric cancer. The expressions of GDF15 and its receptor glial cell-derived neurotrophic factor family receptor a-like (GFRAL) in gastric tumors are important for malignant progression. Moreover, GDF15 expression is increased in gastric cancer cells with cisplatin resistance, resulting from elevated intracellular glutathione (GSH) and antioxidant activities. Upregulated GDF15 could increase intracellular GSH content by activating the GFRAL-GCN2-eIF2α-ATF4 signaling, enhancing cystine-uptake transporter xCT expression, and contributing biosynthesis of GSH in human gastric cancer cells. In conclusion, our results indicate that GDF15 could induce chemoresistance by upregulating xCT expression and GSH biosynthesis in human gastric cancer cells. Targeting GDF15 could be a promising treatment method for gastric cancer progression.

Keywords:  chemoresistance; gastric cancer; glial cell-derived neurotrophic factor family receptor a-like; growth differentiation factor 15; xCT

DOI:  https://doi.org/10.1111/cas.15869
Cell Signal. 2023 May 30. pii: S0898-6568(23)00151-1. [Epub ahead of print] 110737

Exosomal B7-H3 facilitates colorectal cancer angiogenesis and metastasis through AKT1/mTOR/VEGFA pathway.

Rendi Wu, Yawen Zhang, XinYi Xu, Qingjun You, Chunjing Yu, Weipeng Wang, Yong Mao.

  B7-H3 (CD276), an immune checkpoint molecule, is aberrantly overexpressed in many types of cancer, and plays important roles in tumor immune evasion, carcinogenesis and metastasis, as well as angiogenesis. However, the mechanisms underlying B7-H3-promoted angiogenesis are still largely unknown. In this study, based on the observation of overexpression of B7-H3 on the tumor cells and vascular endothelial cells (VECs) in colorectal cancer (CRC) tissues, we investigated the roles of cancer cell-drived exosomal B7-H3 in tumor angiogenesis and metastasis through crosstalk between cancer cells and VECs. We found that CRC cell-drived exosomal B7-H3 was uptaken by human umbilical vein endothelial cells (HUVECs) and consequently activated the AKT serine/threonine kinase 1 (AKT1) / mechanistic target of rapamycin kinase (mTOR) / vascular endothelial growth factor A (VEGFA) signaling pathway, thus augmenting the abilities of migration, invasion and tube formation of HUVECs. Furthermore, administration of CRC cell-drived exosomes overexpressing B7-H3 promoted the pulmonary angiogenesis and metastasis of CRC cells in mice. In addition, high expression of B7-H3 was observed in urinary exosomes from CRC patients. Our findings reveal that CRC-derived exosomal B7-H3 promotes tumor angiogenesis and metastasis by activating the AKT1/mTOR/VEGFA signaling pathway. It provides novel insights into the roles of CRC-drived exosomes in CRC progression.

Keywords:  Angiogenesis; B7-H3; Colorectal cancer; Exosome; Metastasis

DOI:  https://doi.org/10.1016/j.cellsig.2023.110737
Endocr Rev. 2023 Jun 01. pii: bnad015. [Epub ahead of print]

Update on Adipose Tissue and Cancer.

Kristy A Brown, Philipp E Scherer.

  Adipose tissue is the largest endocrine organ and an accepted contributor to overall energy homeostasis. There is strong evidence linking increased adiposity to the development of 13 types of cancer. With increased adiposity comes metabolic dysfunction and insulin resistance, and increased systemic insulin and glucose support the growth of many cancers, including those of the colon and endometrium. There is also an important direct crosstalk between adipose tissue and various organs. For example, the healthy development and function of the mammary gland, as well as the development, growth and progression of breast cancer, are heavily impacted by the breast adipose tissue in which breast epithelial cells are embedded. Cells of the adipose tissue are responsive to external stimuli, including overfeeding, leading to remodeling and important changes in the secretion of factors known to drive the development and growth of cancers. Loss of factors like adiponectin and increased production of leptin, endotrophin, steroid hormones, inflammatory mediators, have been determined to be important mediators of the obesity-cancer link. Obesity is also associated with a structural remodeling of the adipose tissue, including increased localized fibrosis and disrupted angiogenesis that contribute to the development and progression of cancers. Furthermore, tumor cells feed off the adipose tissue, where increased lipolysis within adipocytes leads to the release of fatty acids and stromal cell aerobic glycolysis leading to the increased production of lactate. Both have been hypothesized to support the higher energetic demands of cancer cells.

Keywords:  Adipose tissue; adipokines; cancer; obesity

DOI:  https://doi.org/10.1210/endrev/bnad015
Front Cell Dev Biol. 2023 ;11 1187989

Lipid metabolism and tumor immunotherapy.

Yue Wang, Zongjin Guo, Adamu Danbala Isah, Shuangwei Chen, Yongfei Ren, Huazhong Cai.

  In recent years, the relationship between lipid metabolism and tumour immunotherapy has been thoroughly investigated. An increasing number of studies have shown that abnormal gene expression and ectopic levels of metabolites related to fatty acid synthesis or fatty acid oxidation affect tumour metastasis, recurrence, and drug resistance. Tumour immunotherapy that aims to promote an antitumour immune response has greatly improved the outcomes for tumour patients. However, lipid metabolism reprogramming in tumour cells or tumour microenvironment-infiltrating immune cells can influence the antitumour response of immune cells and induce tumor cell immune evasion. The recent increase in the prevalence of obesity-related cancers has drawn attention to the fact that obesity increases fatty acid oxidation in cancer cells and suppresses the activation of immune cells, thereby weakening antitumour immunity. This article reviews the changes in lipid metabolism in cells in the tumour microenvironment and describes the relationship between lipid metabolism reprogramming in multiple cell types and tumour immunotherapy.

Keywords:  combination therapy; immune cells; immunotherapy; lipid metabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2023.1187989
Front Immunol. 2023 ;14 1166440

Obesity contributes to hepatocellular carcinoma development via immunosuppressive microenvironment remodeling.

Jian Yang, Jialuo He, Yiting Feng, Ming Xiang.

  It is generally recognized that the initiation of obesity-related hepatocellular carcinoma (HCC) is closely associated with hepatic inflammation. However, the paradoxical role of inflammation in the initiation and progression of HCC is highlighted by the fact that the inflammatory HCC is accompanied by significant immune effector cells infiltration compared to non-inflammatory HCC and HCC with enhanced immune response exhibits better survival. Importantly, the cancer progression has been primarily attributed to the immunosuppression, which can also be induced by obesity. Furthermore, the increased risk of viral infection and thus viral-HCC in obese individuals supports the view that obesity contributes to HCC via immunosuppression. Here, we have reviewed the various mechanisms responsible for obesity-induced tumor immune microenvironment and immunosuppression in obesity-related HCC. We highlight that the obesity-induced immunosuppression originates from lipid disorder as well as metabolic reprogramming and propose potential therapeutic strategy for HCC based on the current success of immunotherapy.

Keywords:  fatty acid; immune dysfunction; immunotherapy; metabolic shift; obesity; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1166440
Elife. 2023 May 31. pii: e81289. [Epub ahead of print]12

Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.

Juan J Apiz Saab, Lindsey N Dzierozynski, Patrick B Jonker, Roya AminiTabrizi, Hardik Shah, Rosa Elena Menjivar, Andrew J Scott, Zeribe C Nwosu, Zhou Zhu, Riona N Chen, Moses Oh, Colin Sheehan, Daniel R Wahl, Marina Pasca di Magliano, Costas A Lyssiotis, Kay F Macleod, Christopher R Weber, Alexander Muir.

  Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors (M. R. Sullivan, Danai, et al., 2019). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.

Keywords:  biochemistry; cancer biology; chemical biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.81289
Nat Med. 2023 May 29.

Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance.

Yanshuo Chu, Enyu Dai, Yating Li, Guangchun Han, Guangsheng Pei, Davis R Ingram, Krupa Thakkar, Jiang-Jiang Qin, Minghao Dang, Xiuning Le, Can Hu, Qing Deng, Ansam Sinjab, Pravesh Gupta, Ruiping Wang, Dapeng Hao, Fuduan Peng, Xinmiao Yan, Yunhe Liu, Shumei Song, Shaojun Zhang, John V Heymach, Alexandre Reuben, Yasir Y Elamin, Melissa P Pizzi, Yang Lu, Rossana Lazcano, Jian Hu, Mingyao Li, Michael Curran, Andrew Futreal, Anirban Maitra, Amir A Jazaeri, Jaffer A Ajani, Charles Swanton, Xiang-Dong Cheng, Hussein A Abbas, Maura Gillison, Krishna Bhat, Alexander J Lazar, Michael Green, Kevin Litchfield, Humam Kadara, Cassian Yee, Linghua Wang.

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.

DOI: https://doi.org/10.1038/s41591-023-02371-y
Regen Biomater. 2023 ;10 rbad043

Metformin promotes angiogenesis by enhancing VEGFa secretion by adipose-derived stem cells via the autophagy pathway.

Zihan Tao, Lei Liu, Minliang Wu, Qianqian Wang, Yuchong Wang, Jiachao Xiong, Chunyu Xue.

  Human adipose tissue-derived stem cell (ADSC) derivatives are cell-free, with low immunogenicity and no potential tumourigenicity, making them ideal for aiding wound healing. However, variable quality has impeded their clinical application. Metformin (MET) is a 5' adenosine monophosphate-activated protein kinase activator associated with autophagic activation. In this study, we assessed the potential applicability and underlying mechanisms of MET-treated ADSC derivatives in enhancing angiogenesis. We employed various scientific techniques to evaluate the influence of MET on ADSC, assess angiogenesis and autophagy in MET-treated ADSC in vitro, and examine whether MET-treated ADSC increase angiogenesis. We found that low MET concentrations exerted no appreciable effect on ADSC proliferation. However, MET was observed to enhance the angiogenic capacity and autophagy of ADSC. MET-induced autophagy was associated with increased vascular endothelial growth factor A production and release, which contributed to promoting the therapeutic efficacy of ADSC. In vivo experiments confirmed that in contrast to untreated ADSC, MET-treated ADSC promoted angiogenesis. Our findings thus indicate that the application of MET-treated ADSC would be an effective approach to accelerate wound healing by promoting angiogenesis at wound sites.

Keywords:  angiogenesis; human adipose tissue-derived stem cell; metformin; stem cell; wound healing

DOI:  https://doi.org/10.1093/rb/rbad043