bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒08‒09
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Mol Oncol. 2020 Aug 07.
    Navarro R, Tapia-Galisteo A, Martín-García L, Tarín C, Corbacho C, Gómez-López G, Sánchez-Tirado E, Campuzano S, González-Cortés A, Yáñez-Sedeño P, Compte M, Álvarez-Vallina L, Sanz L.
      The crosstalk between cancer cells and the tumor microenvironment has been implicated in cancer progression and metastasis. Fibroblasts and immune cells are widely known to be attracted to and modified by cancer cells. However, the role of pericytes in the tumor microenvironment beyond endothelium stabilization is poorly understood. Here, we report that pericytes promoted colorectal cancer (CRC) cell proliferation, migration, invasion, stemness and chemoresistance in vitro, as well as tumor growth in a xenograft CRC model. We demonstrate that co-culture with human CRC cells induced broad transcriptomic changes in pericytes, mostly associated with TGF-β receptor activation. The prognostic value of a TGF-β response signature in pericytes was analyzed in CRC patient datasets. This signature was found to be a good predictor of CRC relapse. Moreover, in response to stimulation by CRC cells, pericytes expressed high levels of TGF-β1, initiating an autocrine activation loop. Investigation of secreted mediators and underlying molecular mechanisms revealed that IGFBP-3 is a key paracrine factor from activated pericytes affecting CRC cell migration and invasion. In summary, we demonstrate that the interplay between pericytes and CRC cells triggers a vicious cycle which stimulates pericyte cytokine secretion, in turn increasing CRC cell tumorigenic properties. Overall, we provide another example of how cancer cells can manipulate the tumor microenvironment.
    Keywords:  IGFBP-3; TGF-β; colorectal cancer; pericyte; tumor microenvironment
  2. Crit Rev Immunol. 2020 ;40(2): 157-166
    Chouaib S.
      The immune system is a potent defense mechanism regulating tumor development and progression. However, immune cells are often functionally compromised in cancer patients, and tumor rejection does not follow successful induction of a CTL response. This is, in part, due to the existing conflict between the tumor system and an unfavorable tumor microenvironment (TME) that is able to neutralize or paralyze the immune system of the host. The recent advances in the field of immune checkpoint inhibitors have changed the focus from targeting the tumor to targeting T lymphocytes. It has been well established that the TME and associated multiple factors contribute to the failures in cancer therapies, including immunotherapy. In this regard, hypoxia, which is a hallmark of solid tumors, is strongly associated with advanced disease stages and poor clinical outcomes. Hypoxia plays a crucial role in tumor promotion and immune escape by conferring tumor resistance, immunosuppression, and tumor heterogeneity, which contribute to the generation of diverse cancer invasion programs and enhanced stroma plasticity. Tumor hypoxic stress interferes with the mesenchymal transition EMT, conferring to cancer cells a high degree of plasticity and the capacity to escape from immune surveillance. Tumors have been also shown to take advantage of hypoxic conditions that impede normal cells. Thus, tumor progression may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of malignant cells that overexpress hypoxia-responsive molecules, such as HIF-1α. Currently, the resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer, and its molecular basis is poorly understood. In this review, I focus on hypoxia as a key process that evolved in the TME, and I discuss how solid tumors use hypoxic stress as a potent saboteur of the antitumor immune reaction by shaping a compromised cytotoxic cell function through the alteration of tumor target susceptibility to cell-mediated cytotoxicity. Exploiting hypoxia-associated tumor escape capacities may hold promise for attenuating tumor heterogeneity and plasticity, overcoming alteration of antitumor cytotoxic response and improving its effectiveness in cancer patients.
  3. Mol Nutr Food Res. 2020 Aug 05. e1900482
    Curley S, Gall J, Byrne R, Yvan-Charvet L, McGillicuddy FC.
      Metabolic inflammation is a classic hallmark of obesity that is associated with numerous cardiometabolic complications. Disturbances in fatty acid and cholesterol metabolism are evident in obesity and likely intricately linked to the development and/or sustainment of metabolic inflammation and insulin resistance. Elevations in triglyceride-rich lipoproteins and reductions in high-density lipoprotein (HDL)-cholesterol in turn are two major disturbances that accompany obesity. We discuss how metabolic dyslipidemia may contribute to metabolic inflammation. We also discuss how aberrant cholesterol homeostasis coupled with excessive fatty acid accumulation prime pro-IL-1β and the evidence to support a synergistic partnership between cholesterol and fatty acids in driving metabolic inflammation. We further review pharmaceutical and nutraceutical strategies aimed at attenuating low-grade inflammation and implications for cardiometabolic complications of obesity. We review the current literature on the importance of the local tissue microenvironment in activating adipose tissue macrophages within obese adipose tissue and the contribution of these local immune cells to metabolic inflammation. We finally discuss the limitations to current biomarkers of metabolic inflammation and the importance of novel sensitive biomarkers in driving obesity sub-type characterization to direct personalized medicine approaches to obesity treatment in the future. This article is protected by copyright. All rights reserved.
    Keywords:  Cholesterol; Metabolic Inflammation; NLRP3 inflammasome; Obesity; fatty acids
  4. PLoS Pathog. 2020 Aug 04. 16(8): e1008695
    Tucey TM, Verma J, Olivier FAB, Lo TL, Robertson AAB, Naderer T, Traven A.
      The NLRP3 inflammasome has emerged as a central immune regulator for sensing virulence factors expressed by microbial pathogens for triggering antimicrobial inflammation. Inflammation can be harmful and therefore this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida's ability to compete for glucose or increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvation-dependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some clinical Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and increased microbial loads for activating NLRP3. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections.
  5. Cell Metab. 2020 Aug 04. pii: S1550-4131(20)30369-7. [Epub ahead of print]32(2): 152-153
    Darcy J, Tseng YH.
      Psychological stress has long been known to reduce adaptability to inflammatory challenges, although the precise mechanism has remained elusive. In a recent issue of Cell, Qing et al. (2020) demonstrate that psychological stress induces secretion of IL-6 from brown adipose tissue, which promotes hepatic gluconeogenesis, and reduces host fitness to inflammatory insults.