bims-stacyt 2021-04-04 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2021‒04‒04
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells.
Macrophage inhibitory cytokine-1 induced by a high-fat diet promotes prostate cancer progression by stimulating tumor-promoting cytokine production from tumor stromal cells.
Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications.
Role of Interleukin-6 in Vascular Health and Disease.
Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties.
Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing.
Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer.

Metabolites. 2021 Mar 26. pii: 198. [Epub ahead of print]11(4):

Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells.

Marie Piecyk, Mouna Triki, Pierre-Alexandre Laval, Helena Dragic, Laura Cussonneau, Joelle Fauvre, Cédric Duret, Nicolas Aznar, Toufic Renno, Serge N Manié, Cédric Chaveroux, Carole Ferraro-Peyret.

  Genetic alterations in non-small cell lung cancers (NSCLC) stimulate the generation of energy and biomass to promote tumor development. However, the efficacy of the translation process is finely regulated by stress sensors, themselves often controlled by nutrient availability and chemotoxic agents. Yet, the crosstalk between therapeutic treatment and glucose availability on cell mass generation remains understudied. Herein, we investigated the impact of pemetrexed (PEM) treatment, a first-line agent for NSCLC, on protein synthesis, depending on high or low glucose availability. PEM treatment drastically repressed cell mass and translation when glucose was abundant. Surprisingly, inhibition of protein synthesis caused by low glucose levels was partially dampened upon co-treatment with PEM. Moreover, PEM counteracted the elevation of the endoplasmic reticulum stress (ERS) signal produced upon low glucose availability, providing a molecular explanation for the differential impact of the drug on translation according to glucose levels. Collectively, these data indicate that the ERS constitutes a molecular crosstalk between microenvironmental stressors, contributing to translation reprogramming and proteostasis plasticity.

Keywords:  ER stress signaling; NSCLC; glucose availability; pemetrexed; protein synthesis

DOI:  https://doi.org/10.3390/metabo11040198
Cancer Commun (Lond). 2021 Mar 27.

Macrophage inhibitory cytokine-1 induced by a high-fat diet promotes prostate cancer progression by stimulating tumor-promoting cytokine production from tumor stromal cells.

Mingguo Huang, Shintaro Narita, Atsushi Koizumi, Taketoshi Nara, Kazuyuki Numakura, Shigeru Satoh, Hiroshi Nanjo, Tomonori Habuchi.

  BACKGROUND: Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation.METHODS: We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.
RESULTS: HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor α-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy.
CONCLUSION: HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.

Keywords:  high-fat diet; macrophage inhibitory cytokine-1; metabolism; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/cac2.12137
Cells. 2021 Mar 19. pii: 678. [Epub ahead of print]10(3):

Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications.

Rachel Shi, Chengheng Liao, Qing Zhang.

  Hypoxia, a common feature of solid tumors, greatly hinders the efficacy of conventional cancer treatments such as chemo-, radio-, and immunotherapy. The depletion of oxygen in proliferating and advanced tumors causes an array of genetic, transcriptional, and metabolic adaptations that promote survival, metastasis, and a clinically malignant phenotype. At the nexus of these interconnected pathways are hypoxia-inducible factors (HIFs) which orchestrate transcriptional responses under hypoxia. The following review summarizes current literature regarding effects of hypoxia on DNA repair, metastasis, epithelial-to-mesenchymal transition, the cancer stem cell phenotype, and therapy resistance. We also discuss mechanisms and pathways, such as HIF signaling, mitochondrial dynamics, exosomes, and the unfolded protein response, that contribute to hypoxia-induced phenotypic changes. Finally, novel therapeutics that target the hypoxic tumor microenvironment or interfere with hypoxia-induced pathways are reviewed.

Keywords:  chemoresistance; hypoxia; hypoxia-inducible factors; metastasis

DOI:  https://doi.org/10.3390/cells10030678
Front Mol Biosci. 2021 ;8 641734

Role of Interleukin-6 in Vascular Health and Disease.

Paulina Villar-Fincheira, Fernanda Sanhueza-Olivares, Ignacio Norambuena-Soto, Nicole Cancino-Arenas, Felipe Hernandez-Vargas, Rodrigo Troncoso, Luigi Gabrielli, Mario Chiong.

  IL-6 is usually described as a pleiotropic cytokine produced in response to tissue injury or infection. As a pro-inflammatory cytokine, IL-6 activates innate and adaptative immune responses. IL-6 is released in the innate immune response by leukocytes as well as stromal cells upon pattern recognition receptor activation. IL-6 then recruits immune cells and triggers B and T cell response. Dysregulated IL-6 activity is associated with pathologies involving chronic inflammation and autoimmunity, including atherosclerosis. However, IL-6 is also produced and released under beneficial conditions, such as exercise, where IL-6 is associated with the anti-inflammatory and metabolic effects coupled with physical adaptation to intense training. Exercise-associated IL-6 acts on adipose tissue to induce lipogenesis and on arteries to induce adaptative vascular remodeling. These divergent actions could be explained by complex signaling networks. Classical IL-6 signaling involves a membrane-bound IL-6 receptor and glycoprotein 130 (gp130), while trans-signaling relies on a soluble version of IL-6R (sIL-6R) and membrane-bound gp130. Trans-signaling, but not the classical pathway, is regulated by soluble gp130. In this review, we discuss the similarities and differences in IL-6 cytokine and myokine signaling to explain the differential and opposite effects of this protein during inflammation and exercise, with a special focus on the vascular system.

Keywords:  exercise; gp130; interleukin-6; soluble IL-6 receptor; vascular remodeling; vascular smooth muscle cells

DOI:  https://doi.org/10.3389/fmolb.2021.641734
Cells. 2021 Mar 10. pii: 613. [Epub ahead of print]10(3):

Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties.

Vasiliki Pantazopoulou, Pauline Jeannot, Rebecca Rosberg, Tracy J Berg, Alexander Pietras.

  Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment.

Keywords:  astrocytes; glioma microenvironment; tumor hypoxia

DOI:  https://doi.org/10.3390/cells10030613
Cancers (Basel). 2021 Mar 04. pii: 1102. [Epub ahead of print]13(5):

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing.

Alexander E Kabakov, Anna O Yakimova.

  Within aggressive malignancies, there usually are the "hypoxic zones"-poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial-mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

Keywords:  autophagy; cancer stem cells; epigenetic regulation; epithelial–mesenchymal transition; exosomes; heat shock transcription factor 1; hypoxia-inducible factor-1; metabolic reprogramming; radioembolization; radiotherapy

DOI:  https://doi.org/10.3390/cancers13051102
Cancers (Basel). 2021 Mar 16. pii: 1346. [Epub ahead of print]13(6):

Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer.

Jasmine Gajeton, Irene Krukovets, Santoshi Muppala, Dmitriy Verbovetskiy, Jessica Zhang, Olga Stenina-Adognravi.

  The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Hyperglycemic patients have a higher risk of developing breast cancer. We have identified a novel miRNA-dependent pathway activated by hyperglycemia that promotes BC angiogenesis and inflammation supporting BC growth. miR-467 is upregulated in endothelial cells (EC), macrophages, BC cells, and in BC tumors. A target of miR-467, thrombospondin-1 (TSP-1), inhibits angiogenesis and promotes resolution of inflammation. Systemic injections of a miR-467 antagonist in mouse models of hyperglycemia resulted in decreased BC growth (p < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (p < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (p < 0.001). BC specimens from hyperglycemic patients had increased miR-467 levels, increased angiogenesis, decreased levels of TSP-1, and increased TAM infiltration in malignant breast tissue in hyperglycemic vs. normoglycemic patients (2.17-fold, p = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, p = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (p < 0.001) and increased 56-fold in adjacent normal tissue (p = 0.008). Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.

Keywords:  breast cancer; hyperglycemia; miRNA; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers13061346