bims-stacyt 2020-06-07 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2020‒06‒07
six papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.
Exosomes in hypoxia-induced remodeling of the tumor microenvironment.
Adipocytes promote tumor progression and induce PD-L1 expression via TNF-α/IL-6 signaling.
Inhibition of long noncoding RNA MALAT1 suppresses high glucose-induced apoptosis and inflammation in human umbilical vein endothelial cells by suppressing the NF-κB signaling pathway.
Myeloid Cell-Derived Arginase in Cancer Immune Response.
Arginase-1+ Exosomes from Reprogrammed Macrophages Promote Glioblastoma Progression.

Cell Rep. 2020 Jun 02. pii: S2211-1247(20)30671-9. [Epub ahead of print]31(9): 107701

Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.

Lisa M Becker, Joyce T O'Connell, Annie P Vo, Margo P Cain, Desiree Tampe, Lauren Bizarro, Hikaru Sugimoto, Anna K McGow, John M Asara, Sara Lovisa, Kathleen M McAndrews, Rafal Zielinski, Philip L Lorenzi, Michael Zeisberg, Sughra Raza, Valerie S LeBleu, Raghu Kalluri.

  The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.

Keywords:  breast cancer; cancer-associated fibroblasts; epigenetic alterations; hypoxia; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2020.107701
Cancer Lett. 2020 May 27. pii: S0304-3835(20)30280-9. [Epub ahead of print]488 1-8

Exosomes in hypoxia-induced remodeling of the tumor microenvironment.

Ashish Kumar, Gagan Deep.

  Exosomes are structurally and functionally pleiotropic nano-sized (~30-150 nm in diameter) extracellular vesicles (EVs) with endosomal origin. These vesicles are secreted by almost all cells and play a significant role in intercellular communication and bio-waste disposal. To a great extent, exosomes represent biological "snapshot" of parent cells, and their cargos (protein, nucleotides, lipids, and metabolites) are loaded uniquely under different pathophysiological conditions. For example, most cancerous cells secrete a higher amount of exosomes loaded with distinct cargos under stressful low oxygen condition i.e. hypoxia, a key characteristic of solid tumors responsible for disease aggressiveness and poor survival. Exosomes secreted under hypoxia (ExoHypoxic) play a vital role in aiding cancer cells crosstalk with its microenvironment constituents to create conditions advantageous for cancer growth and metastatic spread. In this review article, we have highlighted the effects of ExoHypoxic on various tumor microenvironment components involved in angiogenesis, survival, proliferation, pre-metastatic niches preparation, immunomodulation, epithelial-to-mesenchymal transition, invasion, metastasis, and drug resistance. We have also described key ExoHypoxic cargos (miRNA, proteins, etc) and their targets in the receipt cells, responsible for various biological effects. Finally, we have emphasized the applicability of ExoHypoxic as a biomarker of tumor hypoxia and disease prognosis.

Keywords:  Biomarker; Exosomes; HIF-1α; Hypoxia; microRNA

DOI:  https://doi.org/10.1016/j.canlet.2020.05.018
Cancer Cell Int. 2020 ;20 179

Adipocytes promote tumor progression and induce PD-L1 expression via TNF-α/IL-6 signaling.

Zhi Li, Cai Zhang, Jing-Xia Du, Jia Zhao, Meng-Ting Shi, Man-Wen Jin, Hui Liu.

  Background: Obesity confers increased risk for various types of cancer. PD-L1 is a key molecule in tumor immune evasion by inducing T cell exhaustion. The relationship between obesity and PD-L1 is still ambiguous. This study was designed to reveal the development of hepatocellular carcinoma and melanoma in obese mice and to investigate if adipocytes regulate PD-L1 expression and the underlying mechanism.Methods: Monosodium glutamate-induced obese mice were inoculated with H22 tumor cells and High fat diet (HFD)-induced obese mice were inoculated with B16-F1 mouse melanoma cells. Human hepatoma HepG2 cells and B16-F1 cells were treated with conditional media from 3T3-L1 adipocytes (adi-CM). Neutralized anti-TNF-α and anti-IL-6 antibodies and inhibitor of NF-κB or STAT3 were used to reveal the mechanism of effect of adi-CM.
Results: In obese mice, H22 and B16-F1 tumor tissues grew faster and PD-L1 expression in tumor tissue was increased. Adi-CM up-regulated PD-L1 level in HepG2 and B16-F1 cells in vitro. Differentiated 3T3-L1 adipocytes secreted TNF-α and IL-6, and neutralizing TNF-α and/or IL-6 reduced PD-L1 expression in adi-CM-treated cells. p-NF-κB/NF-κB level was downregulated in HepG2 and B16-F1 cells, and p-STAT3/STAT3 level was also decreased in HepG2 cells. In addition, inhibitor of NF-κB or STAT3 reversed the effect of adi-CM on PD-L1 expression.
Conclusions: TNF-α and IL-6 secreted by adipocytes up-regulates PD-L1 in hepatoma and B16-F1 cells, which may be at least partially involved in the role of obesity in promoting tumor progression.

Keywords:  Adipocytes; Hepatocellular carcinoma; IL-6; Melanoma; PD-L1; TNF-α

DOI:  https://doi.org/10.1186/s12935-020-01269-w
Biochem Cell Biol. 2020 Jun 05.

Inhibition of long noncoding RNA MALAT1 suppresses high glucose-induced apoptosis and inflammation in human umbilical vein endothelial cells by suppressing the NF-κB signaling pathway.

Yu-Ping Gong, Ya-Wei Zhang, Xiao-Qing Su, Hai-Bo Gao.

The study aimed to investigate the expression of long noncoding RNA (lncRNA) MALAT1 in high glucose (HG)-induced human vascular endothelial cells (HUVECs) and the role of MALAT1 in the apoptosis of HG-induced HUVECs. HUVECs were cultured and induced via 25 mmol/L HG. After that, HUVECs were transfected with MALAT1 siRNA. MALAT1 expression was detected by qPCR, while expression of Bax, Bcl-2, cleaved-caspase-3, cleaved-caspase-9, p-65 and p-p65was detected by Western blot analysis. Besides, the regulatory role of MALAT1 in cell activity and apoptosis was detected by observed by CCK-8 assay, TUNEL staining and flow cytometry. Furthermore, the expression of inflammatory factors (TNF-α and IL-6) was detected by ELISA. The expression of MALAT1, TNF-α and IL-6 in HUVECs were increased in HG environment. After HG induced-HUVECs were treated with silencing MALAT1, it was found that cell proliferation was increased significantly, the expression of TNF-α, IL-6, Bax, cleaved-caspase-3 and cleaved-caspase-9 was decreased, and apoptosis was decreased. MALAT1 silencing inhibited the expression of p-p65 in HG-induced HUVECs. In conclusion, our study demonstrated that MALAT1 was upregulated in HG-induced HUVECs, and inhibition of MALAT1 could inhibit HG-induced apoptosis and inflammation in HUVECs by suppression of the NF-κB signaling pathway.

DOI: https://doi.org/10.1139/bcb-2019-0403
Front Immunol. 2020 ;11 938

Myeloid Cell-Derived Arginase in Cancer Immune Response.

Tomasz M Grzywa, Anna Sosnowska, Paweł Matryba, Zuzanna Rydzynska, Marcin Jasinski, Dominika Nowis, Jakub Golab.

  Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

Keywords:  T lymphocyte; T-cell metabolism; arginase; arginine; immunosuppression; immunotherapy; tumor immunology

DOI:  https://doi.org/10.3389/fimmu.2020.00938
Int J Mol Sci. 2020 Jun 02. pii: E3990. [Epub ahead of print]21(11):

Arginase-1+ Exosomes from Reprogrammed Macrophages Promote Glioblastoma Progression.

Juliana H Azambuja, Nils Ludwig, Saigopalakrishna S Yerneni, Elizandra Braganhol, Theresa L Whiteside.

  Interactions between tumor cells and tumor-associated macrophages (TAMs) are critical for glioblastoma progression. The TAMs represent up to 30% of the glioblastoma mass. The role of TAMs in tumor progression and in the mechanisms underlying tumor growth remain unclear. Using an in vitro model resembling the crosstalk between macrophages and glioblastoma cells, we show that glioblastoma-derived exosomes (GBex) reprogram M1 (mediate pro-inflammatory function) and M2 (mediate anti-inflammatory function) macrophages, converting M1 into TAMs and augmenting pro-tumor functions of M2 macrophages. In turn, these GBex-reprogrammed TAMs, produce exosomes decorated by immunosuppressive and tumor-growth promoting proteins. TAM-derived exosomes disseminate these proteins in the tumor microenvironment (TME) promoting tumor cell migration and proliferation. Mechanisms underlying the promotion of glioblastoma growth involved Arginase-1+ exosomes produced by the reprogrammed TAMs. A selective Arginase-1 inhibitor, nor-NOHA reversed growth-promoting effects of Arginase-1 carried by TAM-derived exosomes. The data suggest that GBex-reprogrammed Arginase-1+ TAMs emerge as a major source of exosomes promoting tumor growth and as a potential therapeutic target in glioblastoma.

Keywords:  Arginase-1; TAM-derived exosomes; glioblastoma; glioblastoma--derived exosomes (GBex); macrophage reprogramming; tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/ijms21113990