bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022‒11‒13
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. CD36 and Its Role in Regulating the Tumor Microenvironment.
  2. GDF15 alleviates the progression of benign tracheobronchial stenosis by inhibiting epithelial-mesenchymal transition and inactivating fibroblasts.
  3. Glycocalyx Acts as a Central Player in the Development of Tumor Microenvironment by Extracellular Vesicles for Angiogenesis and Metastasis.
  4. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
  5. Secreted immune metabolites that mediate immune cell communication and function.
  6. Inflammation as a Therapeutic Target in Cancer Cachexia.
  7. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
  8. Cancer-derived extracellular succinate: a driver of cancer metastasis.
  1. Curr Oncol. 2022 Oct 27. 29(11): 8133-8145
    CD36 and Its Role in Regulating the Tumor Microenvironment.
    Xinzhi Liao, Sheng Yan, Jialin Li, Chengming Jiang, Sigen Huang, Shengyin Liu, Xiaofeng Zou, Guoxi Zhang, Junrong Zou, Quanliang Liu.
      CD36 is a transmembrane glycoprotein that binds to a wide range of ligands, including fatty acids (FAs), cholesterol, thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2), and plays an important role in lipid metabolism, immune response, and angiogenesis. Recent studies have highlighted the role of CD36 in mediating lipid uptake by tumor-associated immune cells and in promoting tumor cell progression. In cancer-associated fibroblasts (CAFs), CD36 regulates lipid uptake and matrix protein production to promote tumor proliferation. In addition, CD36 can promote tumor cell adhesion to the extracellular matrix (ECM) and induce epithelial mesenchymal transition (EMT). In terms of tumor angiogenesis, CD36 binding to TSP-1 and TSP-2 can both inhibit tumor angiogenesis and promote tumor migration and invasion. CD36 can promote tumor angiogenesis through vascular mimicry (VM). Overall, we found that CD36 exhibits diverse functions in tumors. Here, we summarize the recent research findings highlighting the novel roles of CD36 in the context of tumors.
    Keywords:  CD36; angiogenesis; lipid metabolism; tumor-associated immune cells
    DOI:  https://doi.org/10.3390/curroncol29110642
  2. Exp Cell Res. 2022 Nov 04. pii: S0014-4827(22)00403-7. [Epub ahead of print]421(2): 113410
    GDF15 alleviates the progression of benign tracheobronchial stenosis by inhibiting epithelial-mesenchymal transition and inactivating fibroblasts.
    Jiaxin Liao, Yiling Gan, Mingyu Peng, Mohan Giri, Shu Yang, Lei Gu, Anmao Li, Rui Xiao, Chunyan He, Yishi Li, Yang Bai, Li Xu, Shuliang Guo.
      Benign tracheobronchial stenosis (BTS) is a fatal and incurable disease. Epithelial repair and matrix reconstruction play an important role in the wound repair process. If the interstitial context is not restored and stabilized in time, it can lead to pathological fibrosis. Here we attempted to identify cytokines that are involved in promoting wound repair. Growth differentiation factor 15 (GDF15) is a cytokine secreted by tracheal epithelial cells, which is indispensable for the growth of epithelial cells and inhibits the overgrowth of fibroblasts. GDF15 can counteract transforming growth factor-β (TGFβ1) stimulation of epithelial-mesenchymal transition (EMT) in tracheal epithelial cells and inhibit fibroblast activation via the TGFβ1-SMAD2/3 pathway. In a rat model of tracheal stenosis, GDF15 supplementation alleviated the degree of tracheal stenosis. These results suggest that GDF15 prevents fibroblast hyperactivation and promotes epithelial repair in injured trachea. GDF15 may be a potential therapy to improve benign tracheobronchial stenosis.
    Keywords:  Cytokine; GDF15; Organ damage and repair; Peptide drugs; TGF-β1/Smad2/3 signaling pathways; Tracheobronchial stenosis
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113410
  3. Cancers (Basel). 2022 Nov 03. pii: 5415. [Epub ahead of print]14(21):
    Glycocalyx Acts as a Central Player in the Development of Tumor Microenvironment by Extracellular Vesicles for Angiogenesis and Metastasis.
    Ye Zeng, Yan Qiu, Wenli Jiang, Bingmei M Fu.
      Angiogenesis in tumor growth and progression involves a series of complex changes in the tumor microenvironment. Extracellular vesicles (EVs) are important components of the tumor microenvironment, which can be classified as exosomes, apoptotic vesicles, and matrix vesicles according to their origins and properties. The EVs that share many common biological properties are important factors for the microenvironmental modification and play a vital role in tumor growth and progression. For example, vascular endothelial growth factor (VEGF) exosomes, which carry VEGF, participate in the tolerance of anti-angiogenic therapy (AAT). The glycocalyx is a mucopolysaccharide structure consisting of glycoproteins, proteoglycans, and glycosaminoglycans. Both endothelial and tumor cells have glycocalyx at their surfaces. Glycocalyx at both cells mediates the secretion and uptake of EVs. On the other hand, many components carried by EVs can modify the glycocalyx, which finally facilitates the development of the tumor microenvironment. In this short review, we first summarize the role of EVs in the development of the tumor microenvironment. Then we review how the glycocalyx is associated with the tumor microenvironment and how it is modulated by the EVs, and finally, we review the role of the glycocalyx in the synthesis, release, and uptake of EVs that affect tumor microenvironments. This review aims to provide a basis for the mechanistic study of AAT and new clues to address the challenges in AAT tolerance, tumor angiogenesis and metastasis.
    Keywords:  angiogenesis; extracellular vesicles; glycocalyx; metastasis; microenvironment
    DOI:  https://doi.org/10.3390/cancers14215415
  4. Sci Signal. 2022 Nov 08. 15(759): eabj4220
    Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
    Vivien Low, Zhongchi Li, John Blenis.
      The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.
    DOI:  https://doi.org/10.1126/scisignal.abj4220
  5. Trends Immunol. 2022 Nov 05. pii: S1471-4906(22)00214-9. [Epub ahead of print]
    Secreted immune metabolites that mediate immune cell communication and function.
    Baihao Zhang, Alexis Vogelzang, Sidonia Fagarasan.
      Metabolites are emerging as essential factors for the immune system that are involved in both metabolic circuits and signaling cascades. Accumulated evidence suggests that altered metabolic programs initiated by the activation and maturation of immune cell types are accompanied by the delivery of various metabolites into the local environment. We propose that, in addition to protein/peptide ligands, secreted immune metabolites (SIMets) are essential components of immune communication networks that fine-tune immune responses under homeostatic and pathological conditions. We summarize recent advances in our understanding of SIMets and discuss the potential mechanisms by which some metabolites engage in immunological responses through receptor-, transporter-, and post-translational-mediated regulation. These insights may contribute to understanding physiology and developing effective therapeutics for inflammatory and immune-mediated diseases.
    Keywords:  flux of metabolites; immune cell subsets; modification; receptor; transporter
    DOI:  https://doi.org/10.1016/j.it.2022.10.006
  6. Cancers (Basel). 2022 Oct 26. pii: 5262. [Epub ahead of print]14(21):
    Inflammation as a Therapeutic Target in Cancer Cachexia.
    Gerald Clamon, Margaret M Byrne, Erin E Talbert.
      Cachexia is a common complication of cancer and is associated with poor quality of life and a decrease in survival. Many patients with cancer cachexia suffer from inflammation associated with elevated cytokines, such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Single-agent trials to treat cancer cachexia have not led to substantial benefit as the type of cytokine which is elevated has rarely been specified and targeted. Cachexia may also be multifactorial, involving inflammation, anorexia, catabolism, depression, and pain, and targeting the multiple causes will likely be necessary to achieve improvement in weight and appetite. A PUBMED search revealed over 3000 articles on cancer cachexia in the past ten years. We attempted to review any studies related to inflammation and cancer cachexia identified by Google Scholar and PUBMED and further search for articles listed in their references. The National Comprehensive Cancer Network (NCCN) guidelines do not provide any suggestion for managing cancer cachexia except a dietary consult. A more targeted approach to developing therapies for cancer cachexia might lead to more personalized and effective therapy.
    Keywords:  cancer-associated weight loss; cytokines; tissue wasting
    DOI:  https://doi.org/10.3390/cancers14215262
  7. Cell Metab. 2022 Nov 02. pii: S1550-4131(22)00461-2. [Epub ahead of print]
    Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
    Zaili Yang, Yazhen Huo, Shixin Zhou, Jingya Guo, Xiaotu Ma, Tao Li, Congli Fan, Likun Wang.
      A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicles and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.
    Keywords:  ER stress; HMGCR; IRE1α; MDSC; XBP1; cancer immunosuppression; cholesterol; macropinocytosis; small extracellular vesicle; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.010
  8. J Biomed Sci. 2022 Nov 07. 29(1): 93
    Cancer-derived extracellular succinate: a driver of cancer metastasis.
    Cheng-Chin Kuo, Jing-Yiing Wu, Kenneth K Wu.
      Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
    Keywords:  Cancer metastasis; G-protein-coupled receptor 91 (GPR91); Hereditary paraganglioma; Succinate; Succinate dehydrogenase; Succinate receptor-1
    DOI:  https://doi.org/10.1186/s12929-022-00878-z
This page is being maintained by Thomas Krichel. It was last updated on 2022‒12‒18 at 22:05:06.