Transforming Growth Factor-β1, Transforming Growth Factor-β2, and Transforming Growth Factor-β3 Enhance Ovarian Cancer Metastatic Potential by Inducing a Smad3-Dependent Epithelial-to-Mesenchymal Transition

Abstract

Transforming growth factor-B (TGF-B) is thought to play a role in the pathobiological progression of ovarian cancer because this peptide hormone is overexpressed in cancer tissue, plasma, and peritoneal fluid. In the current study, we investigated the role of the TGF-B/ Smad3 pathway in ovarian cancer metastasis by regulation of an epithelial-to-mesenchymal transition. When cancer cells were cultured on plastic, TGF-B1, TGF-B2, and TGF-B3 induced pro -matrix metalloproteinase (MMP) secretion, loss of cell-cell junctions, down-regulation of E-cadherin, up-regulation of N-cadherin, and acquisition of a fibroblastoid phenotype, consistent with an epithelial-tomesenchymal transition. Furthermore, Smad3 small interfering RNA transfection inhibited TGF-B -mediated changes to a fibroblastic morphology, but not MMP secretion. When cancer cells were cultured on a three-dimensional collagen matrix, TGF-B1, TGF-B2, and TGF-B3 stimulated both pro-MMP and active MMP secretion and invasion. Smad3 small interfering RNA transfection of cells cultured on a collagen matrix abrogated TGF-B -stimulated invasion and MMP secretion. Analysis of Smad3 nuclear expression in microarrays of serous benign tumors, borderline tumors, and cystadenocarcinoma revealed that Smad3 expression could be used to distinguish benign and borderline tumors from carcinoma (P = 0.006). Higher Smad3 expression also correlated with poor survival (P = 0.031). Furthermore, a direct relationship exists between Smad3 nuclear expression and expression of the mesenchymal marker N-cadherin in cancer patients (P = 0.0057). Collectively, these results implicate an important role for the TGF-B/Smad3 pathway in mediating ovarian oncogenesis by enhancing metastatic potential. (Mol Cancer Res 2008;6(5):695 -705)

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

“…Our findings are consistent with a similar role for ZNF652 as a suppressor of breast cancer cell invasion. We demonstrate that ZNF652 directly represses TGFB1, TGFB2, TGFBR2, EGFR, SMAD2 and VIM; genes that have all been previously implicated in the promotion of mesenchymal transformation and invasion (6,(31)(32)(33)(34). As such, we have defined a new role for ZNF652 as a master regulator of the EMT gene network.…”

MALDI-MSI and Ovarian Cancer Biomarkers

“…Similarly, TGF-β produced by Treg cells stimulates tumor cell proliferation and increases matrix metalloproteinase's (MMP) production and enhances invasiveness of ovarian cancer cells [89][90][91][92][93] . In ovarian cancer, IL7 acts as a growth factor, like in breast cancer, and has been found in ascites and plasma 39,94,95 .…”

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats

“…As uncovered in our previous studies [4,30], melatonin treatment led to an increase of its circulating levels in both melatonin-treated groups, and was sufficient to TGF-β1 is overexpressed in cancer tissue, blood, and peritoneal fluid and it may contribute to OC progression and metastasis, in particular due to the regulation of the epithelial-to-mesenchymal transition [19]. Furthermore, TGF-β1 stimulates matrix metalloproteinase secretion thereby promoting OC cell invasion [38].…”