7042

TGFB2

transforming growth factor, beta 2;TGFB2;transforming growth factor, beta 2

BSC-1 cell growth inhibitor|G-TSF|cetermin|glioblastoma-derived T-cell suppressor factor|polyergin|prepro-transforming growth factor beta-2|transforming growth factor beta-2

1q41

protein-coding

metastatic ovarian granulosa cell tumors (GCT) exhibit loss of betaglycan. Here we test the hypothesis that betaglycan blocks GCT metastasis by suppressing NFkappaB/TGFbeta2-induced matrix metalloprotinease-2 (MMP2). Human GCT and a human GCT cell model demonstrated prominent MMP2 expression, which was dependent on NFkappaB activity and stimulated by TGFbeta2 in an NFkappaB-dependent manner. Betaglycan suppressed both basal and TGFbeta2-induced MMP2 expression and countered metastatic behaviors of GCT cells in non-adherent spheroid culture and in vivo xenograft models of metastasis. These data suggest that NFkappaB/TGFbeta2 promotes, and betaglycan impedes, the early stages of GCT metastasis, when tumor cells first invade the peritoneum.

Transforming growth factor-beta (TGF-beta) 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-beta/Smad3 pathway in ovarian cancer metastasis by regulation of an epithelial-to-mesenchymal transition. When cancer cells were cultured on plastic, TGF-beta1, TGF-beta2, and TGF-beta3 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-to-mesenchymal transition. Furthermore, Smad3 small interfering RNA transfection inhibited TGF-beta-mediated changes to a fibroblastic morphology, but not MMP secretion. When cancer cells were cultured on a three-dimensional collagen matrix, TGF-beta1, TGF-beta2, and TGF-beta3 stimulated both pro-MMP and active MMP secretion and invasion. Smad3 small interfering RNA transfection of cells cultured on a collagen matrix abrogated TGF-beta-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-beta/Smad3 pathway in mediating ovarian oncogenesis by enhancing metastatic potential.

metastatic ovarian granulosa cell tumors (GCT) exhibit loss of betaglycan. Here we test the hypothesis that betaglycan blocks GCT metastasis by suppressing NFkappaB/TGFbeta2-induced matrix metalloprotinease-2 (MMP2). Human GCT and a human GCT cell model demonstrated prominent MMP2 expression, which was dependent on NFkappaB activity and stimulated by TGFbeta2 in an NFkappaB-dependent manner. Betaglycan suppressed both basal and TGFbeta2-induced MMP2 expression and countered metastatic behaviors of GCT cells in non-adherent spheroid culture and in vivo xenograft models of metastasis. These data suggest that NFkappaB/TGFbeta2 promotes, and betaglycan impedes, the early stages of GCT metastasis, when tumor cells first invade the peritoneum.

Three mammalian isoforms of transforming growth factor-beta (TGFbeta) are known, TGFbeta1, 2, and 3, that have non-overlapping functions during development. However, their specific roles in cancers such as prostate cancer are less clear. Here we show that primary cultures of prostatic epithelial cells preferentially produce and activate the latent TGFbeta2 isoform. Paired cultures of normal and malignant prostate cells from prostate cancer patients produced predominantly the TGFbeta2 isoform, with 30- to 70-fold less TGFbeta1. By mono-Q ion exchange chromatography, three major peaks of latent TGFbeta2 activity were observed corresponding to the known small latent TGFbeta2 complex, the known large latent TGFbeta2 complex and a novel eluting peak of latent TGFbeta2. Although prostate cells are known to activate latent TGFbeta, the mechanism for activation is currently unclear. We investigated whether prostate specific antigen (PSA), a serine protease used as a clinical marker for prostate cancer, could play a role in the activation of latent TGFbeta. Unlike plasmin, a known activator of both latent TGFbeta1 and 2, PSA specifically activated the recombinant small latent form of TGFbeta2, but not TGFbeta1. Prostate epithelial cells, therefore, preferentially produce the TGFbeta2 isoform and PSA, a protease produced by the prostate, specifically targets the activation of this TGFbeta isoform. PSA-mediated activation of latent TGFbeta2 may be an important mechanism for autocrine TGFbeta regulation in the prostate and may potentially contribute to the formation of osteoblastic lesions in bone metastatic prostate cancer.