bims-stacyt 2020-05-10 papers

Cell Metab. 2020 Apr 23. pii: S1550-4131(20)30186-8. [Epub ahead of print]

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion.

Aharon Helman, Andrew L Cangelosi, Jeffrey C Davis, Quan Pham, Arielle Rothman, Aubrey L Faust, Juerg R Straubhaar, David M Sabatini, Douglas A Melton.

A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system of the neonate. Despite their central role in metabolic homeostasis, little is known about how pancreatic β cells adjust to the new nutritional challenge. Here, we find that after birth β cell function shifts from amino acid- to glucose-stimulated insulin secretion in correlation with the change in the nutritional environment. This adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway, which leads to intermittent mTORC1 activity. Disrupting nutrient sensitivity of mTORC1 in mature β cells reverts insulin secretion to a functionally immature state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived β cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrients regulate β cell function, thereby enabling a metabolic adaptation for the newborn.

Keywords: embryo; in vitro differentiation; insulin secretion; mTORC1; maturation; nutrient sensing; pancreas; stem cell-derived β cells; β cells

DOI: https://doi.org/10.1016/j.cmet.2020.04.004

Gan To Kagaku Ryoho. 2020 Jan;47(1): 6-10

[The Warburg Effect and M2 Macrophage Polarization in Head and Neck Cancer].

Toshimitsu Ohashi, Norimitsu Inoue, Mitsuhiro Aoki.

Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect. The Warburg effect is caused by tumor cells not only to adapt their metabolism to the demand for and limited supply of oxygen but also to obtain large amounts of nucleotides, amino acids and lipids for excessive proliferation of tumor cells. The Warburg effect results in increased production of lactic acid, as the final product of glycolysis, in the tumor microenvironment. Lactic acid secreted by tumor cells functions as an immunosuppressive mediator and converts macrophages into M2 macrophages. M2 macrophages reduce inflammatory responses and adaptive Th1 immunity, and promote angiogenesis and tissue remodeling. Tumor-associated macrophages(TAMs)polarize into the M2 phenotype and suppress the host anti-cancer immune response, leading to tumor progression. We have demonstrated that tumor-secreted lactic acid is linked to the induction of M2-macrophage polarization in human head and neck squamous cell carcinoma(HNSCC). FDG, which is a glucose analog, uptake measured by positron emission tomography/computed tomography(PET/CT)indicates the Warburg effect in tumor tissue. M2-macrophage polarization is promoted in HNSCC with increased glucose uptake, maximum standardized uptake value(SUVmax), mean SUV(SUVmean). Tumor cells mediate an immunosuppressive microenvironment via inducing M2-macrophage polarization by reprogramming of glucose metabolism, called Warburg effect.

Oncol Rep. 2020 Apr 28.

Curcumin inhibits pancreatic cancer cell invasion and EMT by interfering with tumor‑stromal crosstalk under hypoxic conditions via the IL‑6/ERK/NF‑κB axis.

Wei Li, Liankang Sun, Jianjun Lei, Zheng Wu, Qingyong Ma, Zheng Wang.

Hypoxic microenvironment and pancreatic stellate cells (PSCs) play important roles in pancreatic cancer progression. PSCs secrete a number of soluble factors, such as interleukin (IL)‑6, to facilitate cancer metastasis. Our previous study revealed that curcumin inhibited the invasive ability of pancreatic cancer cells by modulating epithelial‑to‑mesenchymal transition (EMT)‑related factors. However, whether curcumin could suppress tumor‑stromal crosstalk in pancreatic cancer and the underlying mechanisms have yet to be fully elucidated. The aim of the present study was to evaluate whether curcumin could affect pancreatic cancer cell invasion and EMT by interfering with tumor‑stromal interaction under hypoxic conditions. The PSCs were treated with curcumin under hypoxic conditions. The activation of PSCs was detected by testing the expression of α‑smooth muscle actin by western blotting and immunofluorescence analysis. The wound healing assay was used to evaluate the migratory potential of PSCs. The secretion and expression of IL‑6 by PSCs was detected by ELISA and reverse transcription‑quantitative PCR (RT‑qPCR) analysis. BxPC‑3 and Panc‑1 cells were treated with PSC‑conditioned media (PSC‑CM), IL‑6, IL‑6‑neutralizing antibody or curcumin under conditions of normoxia or hypoxia. Transwell invasion assay was used to examine the invasive potential of pancreatic cancer cells. The activation of phosphorylated (p‑) extracellular signal‑regulated kinase (ERK) and p‑nuclear factor (NF)‑κB were measured by western blot analysis. The expression of EMT‑related genes at the mRNA and protein levels was detected by RT‑qPCR and western blot analysis, respectively. The results of the present study demonstrated that curcumin inhibited the activation and migration of PSCs under hypoxic conditions. Curcumin also suppressed the secretion and expression of IL‑6 in PSCs. In addition, curcumin and IL‑6‑neutralizing antibody treatment suppressed PSC‑CM‑modulated pancreatic cancer invasion, EMT and the changes in the expression of E‑cadherin, vimentin and matrix metallopeptidase‑9. Furthermore, the increase in the levels of p‑ERK and p‑NF‑κB induced by PSC‑CM could be counterbalanced by both curcumin and IL‑6‑neutralizing antibody treatment under hypoxic conditions. Taken together, these data indicate that curcumin plays an important role in suppressing tumor‑stromal crosstalk and pancreatic cancer metastasis by inhibiting the IL‑6/ERK/NF‑κB axis. Blocking the IL‑6/ERK/NF‑κB axis by curcumin may be a promising therapeutic strategy for the treatment of pancreatic cancer.

DOI: https://doi.org/10.3892/or.2020.7600

Mol Cancer Res. 2020 May 04. pii: molcanres.0725.2019. [Epub ahead of print]

Hypoxic cancer-secreted exosomal miR-182-5p promotes glioblastoma angiogenesis by targeting Kruppel-like factor 2 and 4.

Nanxiang Xiong, Junjun Li, Hongliang Yuan, Hao Xu, Hongyang Zhao.

Glioblastoma (GBM) is the most lethal primary brain tumor and has a complex molecular profile. Hypoxia plays a critical role during tumor progression and in the tumor microenvironment (TME). Exosomes released by tumor cells contain informative nucleic acids, proteins and lipids involved in the interaction between cancer and stromal cells, thus leading to TME remodeling. Accumulating evidence indicates that exosomes play a pivotal role in cell-to-cell communication. However, the mechanism by which hypoxia affects tumor angiogenesis via exosomes derived from tumor cells remains largely unknown. In our study, we found that, compared with the parental cells under normoxic conditions, the GBM cells produced more exosomes, and miR-182-5p was significantly up-regulated in the exosomes from GBM cells under hypoxic conditions. Exosomal miR-182-5p directly suppressed its targets Kruppel-like factor 2 and 4 (KLF2 and KLF4), leading to the accumulation of vascular endothelial growth factor receptor (VEGFR), thus promoting tumor angiogenesis. Furthermore, exosome- mediated miR-182-5p also inhibited tight junction-related proteins (such as ZO-1, Occludin, and Claudin-5), thus enhancing vascular permeability and tumor transendothelial migration. Knockdown of miR-182-5p reduced angiogenesis and tumor proliferation. Interestingly, we found elevated levels circulating miR-182-5p in patient' blood serum and cerebrospinal fluid (CSF) samples, and its expression level was inversely related to the prognosis. Implications: Overall, our data clarify the diagnostic and prognostic value of tumor-derived exosome-mediated miR-182-5p and reveal the distinctive crosstalk between tumor cells and HUVECs mediated by tumor-derived exosomes that modulate tumor vasculature.

DOI: https://doi.org/10.1158/1541-7786.MCR-19-0725

Rep Pract Oncol Radiother. 2020 May-Jun;25(3):25(3): 422-427

Interplay between inflammation and cancer.

Igor Piotrowski, Katarzyna Kulcenty, Wiktoria Suchorska.

Tumor-promoting inflammation is one of the hallmarks of cancer. It has been shown that cancer development is strongly influenced by both chronic and acute inflammation process. Progress in research on inflammation revealed a connection between inflammatory processes and neoplastic transformation, the progression of tumour, and the development of metastases and recurrences. Moreover, the tumour invasive procedures (both surgery and biopsy) affect the remaining tumour cells by increasing their survival, proliferation and migration. One of the concepts explaining this phenomena is an induction of a wound healing response. While in normal tissue it is necessary for tissue repair, in tumour tissue, induction of adaptive and innate immune response related to wound healing, stimulates tumour cell survival, angiogenesis and extravasation of circulating tumour cells. It has become evident that certain types of immune response and immune cells can promote tumour progression more than others. In this review, we focus on current knowledge on carcinogenesis and promotion of cancer growth induced by inflammatory processes.

Keywords: ANGPTL4, angiopoietin-like 4; CDH1, cadherin 1; COX, cyclooxygenase; Cancer; EMT, epithelail to mesenchymal transition; EP, receptor - prostaglandin receptor; GI, gastrointensinal cancer; IL-6, interleukin 6; Inflammation; MPO, myeloperoxidase; NADPH, nicotynamide adenine dinucleotide phosphate hydrogen; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK, natural killer cells; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory drugs; PGE2, prostaglandin E2; PTHrP, parathyroid hormone related protein; RNS, reactive nitrogen species; ROS, reactive oxigen species; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor β; TGFBRII, transforming growth factor, beta receptor II; TNF-α, tumour necrosis factor α; TNFR1, Tumor necrosis factor receptor 1; TNFR2, Tumor necrosis factor receptor 2; Tumor reccurence; VEGF, vascular endothelail growth factor; bFGF, fibroblast growth factor; iNOS, inducible nitric oxide synthase

DOI: https://doi.org/10.1016/j.rpor.2020.04.004

Mol Ther Nucleic Acids. 2020 Apr 25. pii: S2162-2531(20)30116-5. [Epub ahead of print]20 649-660

Exosomal MicroRNA-126 from RIPC Serum Is Involved in Hypoxia Tolerance in SH-SY5Y Cells by Downregulating DNMT3B.

Ischemic tolerance in the brain can be induced by transient limb ischemia, and this phenomenon is termed remote ischemic preconditioning (RIPC). It still remains elusive how this transfer of tolerance occurs. Exosomes can cross the blood-brain barrier, and some molecules may transfer neuroprotective signals from the periphery to the brain. Serum miRNA-126 is associated with ischemic stroke, and exosomal miRNA-126 has shown protective effects against acute myocardial infarction. Therefore, this study aims to explore whether exosomal miRNA-126 from RIPC serum can play a similar neuroprotective role. Exosomes were isolated from the venous serum of four healthy young male subjects, both before and after RIPC. Exosomal miRNA-126 was measured by real-time PCR. The miRNA-126 target sequence was predicted by bioinformatics software. SH-SY5Y neuronal cells were incubated with exosomes, and the cell cycle was analyzed by flow cytometry. The expression and activity of DNA methyltransferase (DNMT) 3B, a potential target gene of miRNA-126, were examined in SH-SY5Y cells. The cell viability of SH-SY5Y cells exposed to oxygen-glucose deprivation (OGD) was also investigated. To confirm the association between miRNA-126 and DNMT3B, we overexpressed miRNA-126 in SH-SY5Y cells using lentiviral transfection. miRNA-126 expression was upregulated in RIPC exosomes, and bioinformatics prediction showed that miRNA-126 could bind with DNMT3B. DNMT levels and DNMT3B activity were downregulated in SH-SY5Y cells incubated with RIPC exosomes. After overexpression of miRNA-126 in SH-SY5Y cells, global methylation levels and DNMT3B gene expression were downregulated in these cells, consistent with the bioinformatics predictions. RIPC exosomes can affect the cell cycle and increase OGD tolerance in SH-SY5Y cells. RIPC seems to have neuroprotective effects by downregulating the expression of DNMTs in neural cells through the upregulation of serum exosomal miRNA-126.

Keywords: DNA methyltransferase 3B; exosome; microRNA-126; remote ischemic preconditioning

DOI: https://doi.org/10.1016/j.omtn.2020.04.008