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Transforming growth factor-? in the gastrointestinal and hepatic tumor microenvironment.

ABSTRACT: Transforming growth factor (TGF)-? is a multifunctional cytokine that has important roles in tumor formation, progression, and metastasis. TGF-? is overproduced, and its signaling is deregulated, in a variety of human tumors, including colorectal, gastric, pancreatic, and liver. Therapeutics are being developed to block TGF-? signaling. However, TGF-? also functions as a tumor suppressor in premalignant cells. It is not clear how its function changes from that of a tumor suppressor to a tumor promoter; improvements are needed in our understanding of TGF-? functions in tumor development before we can design inhibitors for use as anticancer therapies. TGF-? regulates not only different tumor-cell autonomous signaling pathways, but also interactions between tumor and host cells, through paracrine mechanisms. We review recent findings about how TGF-? is regulated and its roles in the tumor microenvironment and metastasis, with a focus on gastrointestinal cancers. Improved understanding of TGF-? regulation and how it mediates interaction between cancer epithelial cells, immune cells, and fibroblasts will provide important insights into tumor development and progression.

SUBMITTER: Achyut BR

PROVIDER: S-EPMC6644047 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment.

Achyut Bhagelu Ram BR Yang Li L

Gastroenterology 20110811 4

Transforming growth factor (TGF)-β is a multifunctional cytokine that has important roles in tumor formation, progression, and metastasis. TGF-β is overproduced, and its signaling is deregulated, in a variety of human tumors, including colorectal, gastric, pancreatic, and liver. Therapeutics are being developed to block TGF-β signaling. However, TGF-β also functions as a tumor suppressor in premalignant cells. It is not clear how its function changes from that of a tumor suppressor to a tumor pr ...[more]

PMID: 21839702

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Project description:BackgroundNerve growth factor (NGF) contributes to pain in knee osteoarthritis (KOA) patients. Transforming growth factor-beta (TGF-β) stimulates NGF expression in chondrocytes from KOA patients. However, the correlation between synovial TGF-β and NGF levels has not been sufficiently studied in human KOA patients. Further, the mechanism governing NGF regulation by TGF-β in synovial cells is unclear.MethodsDuring total knee arthroplasty, we extracted the synovial tissue (SYT) of 107 subjects with unilateral Kellgren/Lawrence grade 3-4 KOA confirmed by radiography. We examined the distribution of TGF-β and NGF using immunohistochemistry, and analyzed the relationship between NGF and TGFB mRNA levels. Cultured synovial cells extracted from SYT were exposed to culture medium (control), human recombinant TGF-β (rhTGF-β), rhTGF-β + ALK5 inhibitor SB505124, rhTGF-β + transforming growth factor activating kinase 1 (TAK1) inhibitor (5Z)-7-oxozeaenol, or rhTGF-β + p38 inhibitor SB203580 for 30 min, 6 h and 24 h. NGF mRNA expressed by the cultured cells and NGF protein levels in the cell supernatant were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Phosphorylation of p38 was evaluated by western blotting.ResultsNGF mRNA levels were positively correlated with those of TGFB. Cells expressing TGF-β and NGF protein were observed in the lining layer of SYT. TGF-β stimulated increased NGF mRNA expression and NGF protein production. The ALK5 inhibitor completely suppressed the TGF-β-mediated increase in NGF expression and NGF production in synovial cells. ALK5, TAK1 and p38 inhibitors inhibited the TGF-β-induced phosphorylation of p38, and TAK1 and p38 inhibitors partially inhibited the TGF-β-mediated increase in NGF expression and NGF production in synovial cells.ConclusionTGF-β regulates NGF production via the TGF-β/ALK5 signaling pathway in osteoarthritic synovium. This effect may partially occur through inhibition of the TAK1/p38 pathway in the SYT of KOA patients.

Dataset Information

Transforming growth factor-? in the gastrointestinal and hepatic tumor microenvironment.

Publications

Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment.

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