bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2021–02–14
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Metabolic profiles of regulatory T cells in the tumour microenvironment.
  2. The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia.
  3. Emerging roles of non-coding RNAs in the metabolic reprogramming of tumor-associated macrophages.
  4. Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition.
  5. Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies.
  6. Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors.
  7. IL-6 derived from therapy-induced senescence facilitates the glycolytic phenotype in glioblastoma cells.
  8. Unraveling the molecular mechanisms between inflammation and tumor angiogenesis.
  9. Lactate anions participate in T cell cytokine production and function.
  1. Cancer Immunol Immunother. 2021 Feb 12.
    Metabolic profiles of regulatory T cells in the tumour microenvironment.
    Disha Rao, Fabienne Verburg, Kathrin Renner, Daniel S Peeper, Ruben Lacroix, Christian U Blank.
      Metabolic reprogramming of cancer cells generates a tumour microenvironment (TME) characterised by nutrient restriction, hypoxia, acidity and oxidative stress. While these conditions are unfavourable for infiltrating effector T cells, accumulating evidence suggests that regulatory T cells (Tregs) continue to exert their immune-suppressive functions within the TME. The advantages of Tregs within the TME stem from their metabolic profile. Tregs rely on oxidative phosphorylation for their functions, which can be fuelled by a variety of substrates. Even though Tregs are an attractive target to augment anti-tumour immune responses, it remains a challenge to specifically target intra-tumoral Tregs. We provide a comprehensive review of distinct mechanistic links and pathways involved in regulation of Treg metabolism under the prevailing conditions within the tumour. We also describe how these Tregs differ from the ones in the periphery, and from conventional T cells in the tumour. Targeting pathways responsible for adaptation of Tregs in the tumour microenvironment improves anti-tumour immunity in preclinical models. This may provide alternative therapies aiming at reducing immune suppression in the tumour.
    Keywords:  Acidity; Hypoxia; Metabolism; Nutrient depletion; Oxidative stress; Treg
    DOI:  https://doi.org/10.1007/s00262-021-02881-z
  2. Int J Mol Sci. 2021 Feb 04. pii: 1565. [Epub ahead of print]22(4):
    The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia.
    Aldona Kasprzak.
      Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50-61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called "cachexokines". The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.
    Keywords:  cachexia-inducing factors; cancer cachexia; colorectal cancer; pro-inflammatory cytokines; stromal and cancer cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms22041565
  3. Immunol Lett. 2021 Feb 09. pii: S0165-2478(21)00024-9. [Epub ahead of print]
    Emerging roles of non-coding RNAs in the metabolic reprogramming of tumor-associated macrophages.
    Jiali Li, Zhenyi Lu, Ying Zhang, Lin Xia, Zhaoliang Su.
      Macrophages are the most common immune cells in the tumor microenvironment, and tumor-associated macrophages play an important role in cancer development. Metabolic reprogramming is important for the functional plasticity of macrophages. Studies investigating the relevance of non-coding RNAs (ncRNAs) in human cancer found that ncRNAs can regulate the metabolism of cancer cells and tumor-associated macrophages. NcRNAs include short ncRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs). The most common short ncRNAs are microRNAs, which regulate glucose, lipid, and amino acid metabolism in macrophages by acting on metabolism-related pathways and targeting metabolism-related enzymes and proteins, and are therefore involved in cancer progression. The role of lncRNAs and circRNAs in the metabolism of tumor-associated macrophages remains unclear. LncRNAs affect the glucose metabolism of macrophages, whereas their role in lipid and amino acid metabolism is not clear. CircRNAs regulate amino acid metabolism in macrophages. The roles of ncRNAs in energy metabolism and the underlying mechanisms need to be investigated further. Here, we summarize recent findings on the involvement of ncRNAs in metabolic reprogramming in tumor-associated macrophages, which affect the tumor microenvironment and play important roles in the development of cancer. Improving our understanding of the effects of ncRNAs on metabolic reprogramming of tumor-associated macrophages may facilitate the development of effective clinical therapies.
    Keywords:  Cancer; Metabolic reprogramming; Non-coding RNAs; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.imlet.2021.02.003
  4. Cell Metab. 2021 Feb 02. pii: S1550-4131(21)00011-5. [Epub ahead of print]
    Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition.
    Sergio Crespo-Garcia, Pamela R Tsuruda, Agnieszka Dejda, Rathi D Ryan, Frederik Fournier, Shawnta Y Chaney, Frederique Pilon, Taner Dogan, Gael Cagnone, Priyanka Patel, Manuel Buscarlet, Sonali Dasgupta, Gabrielle Girouard, Surabhi R Rao, Ariel M Wilson, Robert O'Brien, Rachel Juneau, Vera Guber, Alexandre Dubrac, Christian Beausejour, Scott Armstrong, Frederick A Mallette, Christopher B Yohn, Jean-Sebastien Joyal, Dan Marquess, Pedro J Beltran, Przemyslaw Sapieha.
      Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.
    Keywords:  BCL-xL; UBX1967; aging; angiogenesis; cellular senescence; diabetes; p16(INK4A); retina; retinopathy; senolytic
    DOI:  https://doi.org/10.1016/j.cmet.2021.01.011
  5. Front Immunol. 2020 ;11 613114
    Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies.
    Raefa Abou Khouzam, Klaudia Brodaczewska, Aleksandra Filipiak, Nagwa Ahmed Zeinelabdin, Stephanie Buart, Cezary Szczylik, Claudine Kieda, Salem Chouaib.
      The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties. Accordingly, aberrantly vascularized TME induces immunosuppression and maintains a continuous hypoxic state. Normalizing the tumor vasculature to restore its vascular integrity, should hence enhance tumor perfusion, relieving hypoxia, and reshaping anti-tumor immunity. Emerging vascular normalization strategies have a great potential in achieving a stable normalization, resulting in mature and functional blood vessels that alleviate tumor hypoxia. Biomarkers enabling the detection and monitoring of tumor hypoxia could be highly advantageous in aiding the translation of novel normalization strategies to clinical application, alone, or in combination with other treatment modalities, such as immunotherapy.
    Keywords:  angiogenesis; hypoxia; microenvironment; normalization; signatures; tumor suppressors; vessel
    DOI:  https://doi.org/10.3389/fimmu.2020.613114
  6. Nat Immunol. 2021 Feb 11.
    Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors.
    Jang Hyun Park, Hyun-Jin Kim, Chae Won Kim, Hyeon Cheol Kim, Yujin Jung, Hyun-Soo Lee, Yunah Lee, Young Seok Ju, Ji Eun Oh, Sung-Hong Park, Jeong Ho Lee, Sung Ki Lee, Heung Kyu Lee.
      The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T cell-mediated antitumor immune responses but not those of conventional T cells. Specifically, tumor hypoxia activated the γδ T cell protein kinase A pathway at a transcriptional level, resulting in repression of the activatory receptor NKG2D. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T cells. These results reveal a hypoxia-mediated mechanism through which brain tumors and γδ T cells interact and emphasize the importance of γδ T cells for antitumor immunity against brain tumors.
    DOI:  https://doi.org/10.1038/s41590-020-00860-7
  7. Am J Cancer Res. 2021 ;11(2): 458-478
    IL-6 derived from therapy-induced senescence facilitates the glycolytic phenotype in glioblastoma cells.
    Jiayu Gu, Jingyi Wang, Xincheng Liu, Ke Sai, Jialuo Mai, Fan Xing, Zhijie Chen, Xiaozhi Yang, Wanjun Lu, Cui Guo, Wenfeng Liu, Yang Xu, Shouxia Xie, Cheng Hu, Guangmei Yan, Wenbo Zhu.
      Activation of the cyclic adenosine monophosphate (cAMP) pathway induces the glial differentiation of glioblastoma (GBM) cells, but the fate of differentiated cells remains poorly understood. Transcriptome analyses have revealed significant changes in the cell cycle- and senescence-related pathways in differentiated GBM cells induced by dibutyryl cAMP (dbcAMP). Further investigations showed that reactive oxygen species (ROS) derived from enhanced mitochondrial function are involved in senescence induction and proliferation inhibition. Moreover, we found that IL-6 from dbcAMP- or temozolomide (TMZ)-induced senescent cells facilitates the glycolytic phenotype of GBM cells and that inhibiting the IL-6-related pathway hinders the proglycolytic effect of either agent. In patient-derived GBM xenograft models, a specific antibody targeting the IL-6 receptor tocilizumab (TCZ) significantly prolongs the survival time of TMZ-treated mice. Taken together, these results suggest that both the differentiation-inducing agent dbcAMP and the chemotherapy drug TMZ are able to drive GBM cells to senescence, and the latter releases IL-6 to potentiate glycolysis, suggesting that IL-6 is a target for adjuvant chemotherapy in GBM treatment.
    Keywords:  Glioblastoma; IL-6; glycolysis; senescence
  8. Am J Cancer Res. 2021 ;11(2): 301-317
    Unraveling the molecular mechanisms between inflammation and tumor angiogenesis.
    Wenwen Zhou, Longtao Yang, Lin Nie, Hui Lin.
      Inflammatory mediators in tumor microenvironment influence cancer occurrence, growth and metastasis through complex signaling networks. Excessive inflammation is closely associated with elevated cancer risk and mortality, in part through inflammation-induced angiogenesis. Mechanistically, multiple tumor-associated inflammatory cells increase the release and accumulation of various inflammatory products in cancerous sites. These products in turn activate tumor associated signaling cascades such as STAT3, NF-κB, PI3K/Akt and p38 MAPK, which mediate the recruitment of inflammatory cells and secretion of pro-inflammatory factors. More importantly, these events promote the secretion of various pro-angiogenesis factors from endothelial, tumor and inflammatory cells, which then drive malignancy in endothelial cells in a paracrine and/or autocrine manner. Its ultimate effect is to promote endothelial cell proliferation, migration, survival and tube formation, and to hence the formation of blood vessels in tumors. This review describes the signaling network that connects the interaction between inflammation and cancer, especially those involved in inflammation-induced angiogenesis. This will reveal potential targets for the design of anti-inflammatory treatments and drugs that inhibites tumor growth and angiogenesis.
    Keywords:  Inflammation; endothelial cells; signal pathway; tumor angiogenesis
  9. Sci China Life Sci. 2021 Feb 09.
    Lactate anions participate in T cell cytokine production and function.
    Jing Wen, Shipeng Cheng, Yaguang Zhang, Ran Wang, Jiefang Xu, Zhiyang Ling, Liyan Ma, Xinghao Ai, Bing Sun.
      After antigen stimulation, T cells preferentially increase aerobic glycolysis to meet the bioenergetic and biosynthetic demands of T cell activation, proliferation, and effector functions. Lactate, a by-product of glycolysis, has been reported to function as an important energy source and signaling molecule. Here, we found that lactate anions are involved in cytokine production in T cells after TCR activation. During ex vivo T cell activation, the addition of excess sodium lactate (NaL) increased the production of cytokines (such as IFNγ/IL-2/TNFα) more than the addition of sodium chloride (NaCl). This enhanced cytokine production was dependent on TCR/CD3 activation but not CD28 activation. In vivo, NaL treatment inhibited tumour growth in subcutaneously transplanted tumour models in a T cell-dependent manner, which was consistent with increased T cell cytokine production in the NaL treatment group compared to the NaCl treatment group. Furthermore, a mechanistic experiment showed that this enhanced cytokine production was regulated by GAPDH-mediated post-transcriptional regulation. Taken together, our findings indicate a new regulatory mechanism involved in glycolysis that promotes T cell function.
    Keywords:  TCR activation; glycolysis; immunometabolism; lactate
    DOI:  https://doi.org/10.1007/s11427-020-1887-7
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