bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒11‒29
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cell Biol Int. 2020 Nov 25.
    Mortezaee K.
      Tumor cells are needed to cope with the host environment in order to maintain their survival and keep growing in hard conditions. This infers that tumors must acquire characteristics more potent than what seen for normal tissue cells, without which they are condemned to disruption. As for example, cancer cells have more potent redox tolerance compared to normal cells, which is due to their high adaptation to the oxidative crisis. In addition, increased demand for bioenergetics and biosynthesis can cause a rise of nutrient uptake in tumors. Utilizing nutrients in low nutrient conditions infers that tumors are also equipped with adaptive metabolic processes. Switching the metabolic demands toward glucose consumption upon exposure to the hypoxic TME, or changing toward using other sources when there is an over-consumption of glucose in the tumor area are examples of fitness metabolic systems in tumors. In fact, cancer cells in cooperation with their nearby stroma (in a process called metabolic coupling) can reprogram their metabolic systems in their favor. This infers the high importance of stroma for meeting the metabolic demands of a growing tumor, an example in this context is the metabolic symbiosis between cancer associated fibroblasts (CAFs) with cancer cells. The point is that redox tolerance and metabolic reprogramming are inter-related, and that, without a doubt, disruption of redox tolerance systems by transient exposure to either oxidative or antioxidative loading, or targeting metabolic rewiring by modulation of tumor glucose availability, controlling tumor/stroma interactions, etc. can be effective from therapeutic window. This article is protected by copyright. All rights reserved.
    Keywords:  cancer; glycolysis; hallmark; normal cell, mitochondria; oxidative stress; reprogramming; tumor microenvironment (TME)
  2. Exp Cell Res. 2020 Nov 23. pii: S0014-4827(20)30647-9. [Epub ahead of print] 112394
    Zheng H, Yu S, Zhu C, Guo T, Liu F, Xu Y.
      Chemoresistance is a tremendous challenge to efficacy of systemic chemotherapy which is the preferred treatment for the advanced CRC patients. More tumor-associated macrophages (TAMs) are recruited into the CRC tumor under chemotherapy, which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we present that activated HIF1α signaling in CRC cells under chemotherapy drives the expression of HMGB1to promotes macrophage infiltration and in turn chemoresistance development. Chemotherapeutic treatment with 5-FU leads to increased recruitment of macrophages into tumors, which display tumor-protective alternative activation. Mechanistically, tumor HIF1α signaling activated by chemo-induced ROS drives the transcription of HMGB1 to promote more macrophage infiltration into CRC tumor. Furthermore, high levels of GDF15 produced by TAMs impair the chemosensitity of tumor cells via enhancing fatty acids β-oxidation. Together, our current study reveals a new insight into the cross-talking between tumor cells and immune cells, and provides novel drug targets for clinic treatments for CRC.
    Keywords:  Chemoresistance; Colorectal carcinoma; GDF15; HIF1α; TAM
  3. Immunity. 2020 Nov 17. pii: S1074-7613(20)30408-8. [Epub ahead of print]
    Diskin C, Ryan TAJ, O'Neill LAJ.
      Immunometabolism has emerged as a key focus for immunologists, with metabolic change in immune cells becoming as important a determinant for specific immune effector responses as discrete signaling pathways. A key output for these changes involves post-translational modification (PTM) of proteins by metabolites. Products of glycolysis and Krebs cycle pathways can mediate these events, as can lipids, amino acids, and polyamines. A rich and diverse set of PTMs in macrophages and T cells has been uncovered, altering phenotype and modulating immunity and inflammation in different contexts. We review the recent findings in this area and speculate whether they could be of use in the effort to develop therapeutics for immune-related diseases.
  4. Immunity. 2020 Nov 10. pii: S1074-7613(20)30461-1. [Epub ahead of print]
    Bonavita E, Bromley CP, Jonsson G, Pelly VS, Sahoo S, Walwyn-Brown K, Mensurado S, Moeini A, Flanagan E, Bell CR, Chiang SC, Chikkanna-Gowda CP, Rogers N, Silva-Santos B, Jaillon S, Mantovani A, Reis E Sousa C, Guerra N, Davis DM, Zelenay S.
      Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
    Keywords:  NK cells; cancer-related inflammation; cytotoxic T cells; immune evasion; immunotherapy; interferon-gamma; prostaglandin E2; tumor immunity; tumor microenvironment
  5. Cancer Res. 2020 Nov 23. pii: canres.0622.2020. [Epub ahead of print]
    Mestre-Farrera A, Bruch-Oms M, Peña R, Rodríguez-Morató J, Alba-Castellón L, Comerma L, Quintela-Fandino M, Duñach M, Baulida J, Pozo ÓJ, García de Herreros A.
      Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAF and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration towards this amino acid when cultured in low glutamine conditions. CAF also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were co-cultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation which involved the TGFb/Snail1 signaling axis. CAF migration towards Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells towards nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis.
  6. Neuroscience. 2020 Nov 18. pii: S0306-4522(20)30701-6. [Epub ahead of print]
    Douglas AS, Shearer JA, Okolo A, Pandit A, Gilvarry M, Doyle KM.
      We investigated the effect of full and partial mechanical reperfusion on MMP-9 expression in rat brain following middle cerebral artery occlusion, mimicking mechanical thrombectomy. Using percentage hemispheric lesion volume and oedema as measures, partial reperfusion reduced extent of brain damage caused by MCA occlusion, but the protective effect was less pronounced than with complete reperfusion. Using ELISA quantification in fresh frozen tissue, confirmed by immunofluorescence in perfusion fixed tissue, increased MMP-9 expression was observed in infarcted tissue. MMP-9 was increased in lesioned tissue of the anterior and posterior temporal cortex and underlying striatal tissue, but also the normal appearing frontal cortex. No significant increase in MMP-9 in the hippocampus was observed, nor in the unlesioned contralateral hemisphere. Both partial reperfusion and full reperfusion reduced the regional MMP expression significantly. The highest levels of MMP-9 were observed in lesioned brain regions in the non-reperfused group. MMP-9 expression was evident in microvessels and in neuronal cell bodies of affected tissue. This study shows that MMP-9 brain levels are reduced relative to the extent of reperfusion. These observations suggest targeting early increases in MMP-9 expression as a possible neuroprotective therapeutic strategy and highlight the rat MCA occlusion model as an ideal model in which to study candidate therapeutics.
    Keywords:  MCA occlusion rat model; MMP-9; hemispheric lesion volume; ischaemic stroke; reperfusion
  7. J Cell Physiol. 2020 Nov 23.
    Tu CE, Hu Y, Zhou P, Guo X, Gu C, Zhang Y, Li A, Liu S.
      The tumor microenvironment significantly affects tumor progression, and tumor cells can also remodel the tumor microenvironment through complex interaction. Inflammasomes are innate immune system receptors/sensors that regulate an inflammatory response mainly mediated by the nucleotide-binding oligomerization domain-like receptors in macrophages, which can also influence the formation, progression and therapeutic response of cancer. However, the effects of tumor-derived factors in the microenvironment on inflammasomes have rarely been reported. In this study, we found that lactate, as the main metabolite of tumor cells could specifically activate the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3 inflammasome through increasing the level of reactive oxygen species (ROS) in THP-1-derived macrophages. Furthermore, we showed that transforming growth factor-β (TGF-β), a cytokine accumulated in the tumor microenvironment, could be induced by lactate treatment in tumor cells, and in turn inhibit inflammasome activation induced by lactate and other canonical ligands in macrophages. In addition, TGF-β might induce autophagy of macrophages in a SMAD-dependent manner, leading to ROS clearance and eventually inhibiting the activation of inflammasomes. Collectively, these results indicated that in the tumor microenvironment, tumor-derived lactate could act as a danger signal alerting innate immunity, but nevertheless tumor cells produced more TGF-β to avoid immune surveillance.
    Keywords:  autophagy; inflammasome; lactate; reactive oxygen species; transforming growth factor-β