bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2021‒01‒03
three papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Front Cell Dev Biol. 2020 ;8 610661
      Anti-angiogenic therapies (AATs) have been widely used for cancer treatment. But the beneficial effects of AATs are short, because AAT-induced tumor revascularization facilitates the tumor relapse. In this mini-review, we described different forms of tumor neovascularization and revascularization including sprouting angiogenesis, vessel co-option, intussusceptive angiogenesis, and vasculogenic mimicry, all of which are closely mediated by vascular endothelial growth factor (VEGF), angiopoietins, matrix metalloproteinases, and exosomes. We also summarized the current findings for the resistance mechanisms of AATs including enhancement in pro-angiogenic cytokines, heterogeneity in tumor-associated endothelial cells (ECs), crosstalk between tumor cells and ECs, masking of extracellular vesicles, matrix stiffness and contributions from fibroblasts, macrophages and adipocytes in the tumor microenvironment. We highlighted the revascularization following AATs, particularly the role of exosome stimulating factors such as hypoxia and miRNA, and that of exosomal cargos such as cytokines, miRNAs, lncRNAs, and circRNAs from the tumor ECs in angiogenesis and revascularization. Finally, we proposed that renormalization of tumor ECs would be a more efficient cancer therapy than the current AATs.
    Keywords:  anti-angiogenesis; resistance; revascularization; therapy failure; tumor endothelial cell
  2. Curr Opin Biotechnol. 2020 Dec 23. pii: S0958-1669(20)30180-4. [Epub ahead of print]68 181-185
      Mutations in the genes encoding isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are key drivers of diverse cancers, including gliomas and hematological malignancies. IDH mutations cause neomorphic enzymatic activity that results in the production of the oncometabolite 2-hydroxyglutarate (2-HG). In addition to 2-HG's well-known effects on tumor cells themselves, it has become increasingly clear that 2-HG directly influences the tumor microenvironment (TME). In particular, the non-cell-autonomous impact of 2-HG on the immune system likely plays a major role in shaping disease development and response to therapy. It is therefore critical to understand how IDH mutations affect the metabolism, epigenetics, and functions of tumor-infiltrating immune cells. Such knowledge may point towards new therapeutic approaches to treat IDH-mutant cancers.
  3. Biochim Biophys Acta Gen Subj. 2020 Dec 25. pii: S0304-4165(20)30345-7. [Epub ahead of print]1865(3): 129834
      BACKGROUND: Mitochondria is a key organelle for energy production and cellular adaptive response to intracellular and extracellular stresses. Mitochondrial stress can be evoked by various stimuli such as metabolic stressors or pathogen infection, which may lead to expression of 'mitokines' such as growth differentiation factor 15 (GDF15).SCOPE OF REVIEW: This review summarizes the mechanism of GDF15 expression in response to organelle stress such as mitochondrial stress, and covers pathophysiological conditions or diseases that are associated with elevated GDF15 level. This review also illustrates the in vivo role of GDF15 expression in those stress conditions or diseases, and a potential of GDF15 as a therapeutic agent against metabolic disorders such as NASH.
    MAJOR CONCLUSIONS: Mitochondrial unfolded protein response (UPRmt) is a critical process to recover from mitochondrial stress. UPRmt can induce expression of secretory proteins that can exert systemic effects (mitokines) as well as mitochondrial chaperons. GDF15 can have either protective or detrimental systemic effects in response to mitochondrial stresses, suggesting its role as a mitokine. Mounting evidence shows that GDF15 is also induced by stresses of organelles other than mitochondria such as endoplasmic reticulum (ER). GDF15 level is increased in serum or tissue of mice and human subjects with metabolic diseases such as obesity or NASH. GDF15 can modulate metabolic features of those diseases.
    GENERAL SIGNIFICANCE: GDF15 play a role as an integrated stress response (ISR) beyond mitochondrial stress response. GDF15 is involved in the pathogenesis of metabolic diseases such as NASH, and also could be a candidate for therapeutic agent against those diseases.
    Keywords:  ER; GDF15; Metabolic diseases; Mitochondria; NASH; Stress