bims-stacyt 2020-02-16 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–02–16
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Mesenchymal stem cell-derived exosomes rescue oxygen-glucose deprivation-induced injury in endothelial cells.
Crosstalk among colon cancer-derived exosomes, fibroblast-derived exosomes, and macrophage phenotypes in colon cancer metastasis.
Oncogenic Kras driven metabolic reprogramming in pancreas cancer cells utilizes cytokines from the tumor microenvironment.
The Multifaceted Roles of CXCL9 Within the Tumor Microenvironment.
IL-17 Signaling in the Tumor Microenvironment.
BMP9 signaling promotes the normalization of tumor blood vessels.
Transcriptional Regulation of Transforming Growth Factor β1 by Glucose: Investigation into the Role of the Hexosamine Biosynthesis Pathway.

Curr Neurovasc Res. 2020 Feb 13.

Mesenchymal stem cell-derived exosomes rescue oxygen-glucose deprivation-induced injury in endothelial cells.

Li-Yun Kong, Meng-Ya Liang, Jian-Ping Liu, Ping Lai, Jun-Song Ye, Zu-Xiong Zhang, Zhi-Ming Du, Jun-Jian Yu, Liang Gu, Fa-Chun Xie, Zhi-Xian Tang, Zi-You Liu.

   OBJECTIVE: The effects of mesenchymal stem cell (MSC)-derived exosomes on brain microvascular endothelial cells under oxygen-glucose deprivation (OGD), which mimics cells in deep hypothermic circulatory arrest (DHCA) in vitro, are yet to be studied.
METHODS: MSCs were co-cultured with primary rat brain endothelial cells, which were then exposed to OGD. Cell viability, apoptosis, the inflammatory factors (IL-1β, IL-6, and TNF-α), and the activation of inflammation-associated TLR4-mediated pyroptosis and the NF-κB signaling pathway were determined. Furthermore, exosomes derived from MSCs were isolated and incubated with endothelial cells to investigate whether the effect of MSCs is associated with MSC-derived exosomes. Apoptosis, cell viability, and the inflammatory response were also analyzed in OGD-induced endothelial cells incubated with MSC-derived exosomes.
RESULTS: OGD treatment promoted endothelial cell apoptosis, induced the release of inflammatory factors IL-1β, IL-6, and TNF-α, and inhibited cell viability. Western blot analysis showed that OGD treatment induced TLR4, and NF-κB p65 subunit phosphorylation and caspase-1 upregulation, while co-culture with MSCs could reduce the effect of OGD treatment on endothelial cells. As expected, the effect of MSC-derived exosomes on OGD-treated endothelial cells was similar to that of MSCs. MSC-derived exosomes alleviated the OGD-induced decrease in the viability of endothelial cells, and increased levels of apoptosis, inflammatory factors, and the activation of inflammatory and inflammatory focal pathways.
CONCLUSION: Both MSCs and MSC-derived exosomes attenuated OGD-induced rat primary brain endothelial cell injury. These findings suggest that at least some of the protective effects of MSCs on endothelial cells are mediated by MSC-derived exosomes.

Keywords:  Brain; Endothelial cells; Exosome; Inflammatory factors; Mesenchymal stem cells; Oxygen-glucose deprivation

DOI:  https://doi.org/10.2174/1567202617666200214103950
Int Immunopharmacol. 2020 Feb 11. pii: S1567-5769(19)32634-7. [Epub ahead of print]81 106298

Crosstalk among colon cancer-derived exosomes, fibroblast-derived exosomes, and macrophage phenotypes in colon cancer metastasis.

Meiyun Wang, Zhaoliang Su, Prince Amoah Barnie.

  Cellular crosstalk is an important mechanism in the pathogenesis of inflammatory disorders and cancers. One significant means by which cells communicate with each other is through the release of exosomes. Exosomes are extracellular vesicles formed by the outward budding of plasma membranes, which are then released from cells into the extracellular space. Many studies have suggested that microvesicles released by colon cancer cells initiate crosstalk and modulate the fibroblast activities and macrophage phenotypes. Interestingly, crosstalk among colon cancer cells, macrophages and cancer-associated fibroblasts maximizes the mechanical composition of the stromal extracellular matrix (ECM). Exosomes contribute to cancer cell migration and invasion, which are critical for colon cancer progression to metastasis. The majority of the studies on colorectal cancers (CRCs) have focused on developing exosomal biomarkers for the early detection and prediction of CRC prognosis. This study highlights the crosstalk among colon cancer-derived exosomes, macrophage phenotypes and fibroblasts during colon cancer metastasis.

Keywords:  CRC metastasis; Exosomes; Fibroblast; Macrophage phenotype

DOI:  https://doi.org/10.1016/j.intimp.2020.106298
Cancer Discov. 2020 Feb 11. pii: CD-19-0297. [Epub ahead of print]

Oncogenic Kras driven metabolic reprogramming in pancreas cancer cells utilizes cytokines from the tumor microenvironment.

Prasenjit Dey, Jun Li, Jianhua Zhang, Surendra Chaurasiya, Anders Strom, Huamin Wang, Wen-Ting Liao, Frederick Cavallaro, Parker Denz, Vincent Bernard, Er-Yen Yen, Giannicola Genovese, Pat Gulhati, Jielin Liu, Deepavali Chakravarti, Pingna Deng, Tingxin Zhang, Federica Carbone, Qing Chang, Haoqiang Ying, Xiaoying Shang, Denise J Spring, Bidyut Ghosh, Nagireddy Putluri, Anirban Maitra, Y Alan Wang, Ronald A DePinho.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic Kras in pro-tumorigenic signaling interactions between cancer cells and host cells. We show that Kras* drives cell autonomous expression of type I cytokine receptor complexes (IL2ry-IL4ra and IL2ry-IL13ra1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading TH2 cells in the microenvironment. Early neoplastic lesions show close proximity of Kras* cancer cells and TH2 cells producing IL4 and IL13. Activated IL2ry-IL4ra and IL2ry-IL13ra1 receptors signal primarily via Jak1-Stat6. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC.

DOI: https://doi.org/10.1158/2159-8290.CD-19-0297
Adv Exp Med Biol. 2020 ;1231 45-51

The Multifaceted Roles of CXCL9 Within the Tumor Microenvironment.

Shi Yong Neo, Andreas Lundqvist.

  Chemokines are soluble proteins that orchestrate cell migration in a regulated concentration gradient. During early stages of tumor development, chemokines shape the immune landscape of tumor microenvironment. CXCL9, also known as monokine induced by gamma-interferon (MIG), can be produced during inflammatory conditions by myeloid cells within the tumor microenvironment. It attracts cells expressing the CXCR3 receptor including activated T and NK cells and has been shown to play a role in responses to immune checkpoint therapy. Overexpression of CXCL9 has also shown to reduce tumor progression and metastasis via the inhibition of angiogenesis. Conversely, CXCL9 can act directly on tumor cells expressing the CXCR3 receptor to promote cell migration and epithelial mesenchymal transition. In this chapter we discuss the anti- and pro-tumoral features of CXCL9 within the tumor microenvironment.

Keywords:  Angiogenesis; Biomarker; CXC chemokines; CXCL9; CXCR3; Chemokines; Epithelial mesenchymal transition; Inflammation; MIG; Metastasis; Migration; NK cells; T cells; Tumor microenvironment; Tumors

DOI:  https://doi.org/10.1007/978-3-030-36667-4_5
Adv Exp Med Biol. 2020 ;1240 47-58

IL-17 Signaling in the Tumor Microenvironment.

R M Gorczynski.

  Inflammation is recognized as representing a double-edged sword in terms of tumor growth, in some instances contributing to attenuation of growth and in others to enhanced progression and metastasis. Extracellular signals, released by cells within the tumor microenvironment (TME), including cancer cells themselves, as well as infiltrating immune cells, stromal cells, and other components of the extracellular matrix, all can contribute to reshaping the tumor microenvironment (TME) and tumor growth/survival. Most recently, attention has centered on contributions in the TME made by the pro-inflammatory interleukin 17 (IL-17) and the T cells (Th17) and non-T cells which produce this cytokine, as well as the target cells (IL-17 receptor positive, IL-17R+) signaled by IL-17. The IL-17 family itself comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F, all of which are known to be secreted as disulfide-linked homo- or heterodimers. These in turn bind to IL-17R, a type I cell surface receptor, of which at least five variants have been described to date, IL-17RA to IL-17RE. The discussion below focuses on what we know to date about the role of IL-17/IL-17R interactions in the tumor microenvironment in regulation of tumor growth and metastasis and highlights recent ideas concerning the possible utility of this knowledge in the clinic.

Keywords:  Cancer; Checkpoint blockade; Chronic lymphocytic leukemia (CLL); Cytokines; Extracellular signaling; IL-17 isoforms; IL-6; Il-17R isoforms; Immunoregulation; Immunotherapy; Inflammation; Regulatory T cells (Tregs); Tumor growth/survival; Tumor metastasis/invasion; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/978-3-030-38315-2_4
Oncogene. 2020 Feb 10.

BMP9 signaling promotes the normalization of tumor blood vessels.

Claire Viallard, Cindy Audiger, Natalija Popovic, Naoufal Akla, Kevin Lanthier, Isaac Legault-Navarrete, Heather Melichar, Santiago Costantino, Sylvie Lesage, Bruno Larrivée.

The presence of an immature tumor vascular network contributes to cancer dissemination and the development of resistance to therapies. Strategies to normalize the tumor vasculature are therefore of significant therapeutic interest for cancer treatments. VEGF inhibitors are used clinically to normalize tumor blood vessels. However, the time frame and dosage of these inhibitors required to achieve normalization is rather narrow, and there is a need to identify additional signaling targets to attain vascular normalization. In addition to VEGF, the endothelial-specific receptor Alk1 plays a critical role in vascular development and promotes vascular remodeling and maturation. Therefore, we sought to evaluate the effects of the Alk1 ligand BMP9 on tumor vascular formation. BMP9 overexpression in Lewis Lung Carcinoma (LLC) tumors significantly delayed tumor growth. Blood vessels in BMP9-overexpressing LLC tumors displayed markers of vascular maturation and were characterized by increased perivascular cell coverage. Tumor vasculature normalization was associated with decreased permeability and increased perfusion. These changes in vascular function in BMP9-overexpressing LLC tumors resulted in significant alterations of the tumor microenvironment, characterized by a decrease in hypoxia and an increase in immune infiltration. In conclusion, we show that BMP9 promotes vascular normalization in LLC tumors that leads to changes in the microenvironment.

DOI: https://doi.org/10.1038/s41388-020-1200-0
Am J Med Sci. 2020 Feb;pii: S0002-9629(19)30468-9. [Epub ahead of print]359(2): 79-83

Transcriptional Regulation of Transforming Growth Factor β1 by Glucose: Investigation into the Role of the Hexosamine Biosynthesis Pathway.

Marc C Daniels, Donald A McClain, Errol D Crook.

   BACKGROUND: The hexosamine biosynthesis pathway (HBP) is hypothesized to mediate many of the adverse effects of hyperglycemia. We have shown previously that increased flux through this pathway leads to induction of the growth factor transforming growth factor-α (TGF-α) and to insulin resistance in cultured cells and transgenic mice. TGF-β is regulated by glucose and is involved in the development of diabetic nephropathy. We therefore hypothesized that the HBP was involved in the regulation of TGF-β by glucose in rat vascular and kidney cells.
METHODS: A plasmid containing the promoter region of TGF-β1 cloned upstream of the firefly luciferase gene was electroporated into rat aortic smooth muscle, mesangial, and proximal tubule cells. Luciferase activity was measured in cellular extracts from cells cultured in varying concentrations of glucose and glucosamine.
RESULTS: Glucose treatment of all cultured cells led to a time- and dose-dependent stimulation in TGF-β1 transcriptional activity, with high (20 mM) glucose causing a 1.4- to 2.0-fold increase. Glucose stimulation did not occur until after 12 hours and disappeared after 72 hours of treatment. Glucosamine was more potent than glucose, with 3 mM stimulating up to a 4-fold increase in TGFβ1-transcriptional activity. The stimulatory effect of glucosamine was also dose-dependent but was slower to develop and longer lasting than that of glucose.
CONCLUSIONS: The metabolism of glucose through the HBP mediates extracellular matrix production, possibly via the stimulation of TGF-β in kidney cells. Hexosamine metabolism therefore, may play a role in the development of diabetic nephropathy.

Keywords:  Diabetic nephropathy; Glucosamine; Glucose; TGF-β; Vascular cells

DOI:  https://doi.org/10.1016/j.amjms.2019.12.013