Dysfunctional Transforming Growth Factor-β Receptor II Accelerates Prostate Tumorigenesis in the TRAMP Mouse Model

Abstract

The contribution of a dysfunctional transforming growth factor-B type II receptor (TGFBRII) to prostate cancer initiation and progression was investigated in an in vivo mouse model. Transgenic mice harboring the dominantnegative mutant TGF-B type II receptor (DNTGFBRII) in mouse epithelial cell were crossed with the TRAMP prostate cancer transgenic mouse to characterize the in vivo consequences of inactivated TGF-B signaling on prostate tumor initiation and progression. Histopathologic diagnosis of prostate specimens from the TRAMP+/DNTGFBRII double transgenic mice revealed the appearance of early malignant changes and subsequently highly aggressive prostate tumors at a younger age, compared with littermates TRAMP+/Wt TGFBRII mice. Immunohistochemical and Western blotting analysis revealed significantly increased proliferative and apoptotic activities, as well as vascularity and macrophage infiltration that correlated with an elevated vascular endothelial growth factor and MCP-1 protein levels in prostates from TRAMP+/DNTGFBRII+ mice. An epithelialmesenchymal transition (EMT) effect was also detected in prostates of TRAMP+/DNTGFBRII mice, as documented by the loss of epithelial markers (E-cadherin and B-catenin) and up-regulation of mesenchymal markers (N-cadherin) and EMT-transcription factor Snail. A significant increase in the androgen receptor mRNA and protein levels was associated with the early onset of prostate tumorigenesis in TRAMP+/DNTGFBRII mice. Our results indicate that in vivo disruption of TGF-B signaling accelerates the pathologic malignant changes in the prostate by altering the kinetics of prostate growth and inducing EMT. The study also suggests that a dysfunctional TGFBRII augments androgen receptor expression and promotes inflammation in early stage tumor growth, thus conferring a significant contribution by TGF-B to prostate cancer progression.

Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions

“…TGF-b1 functions as a paracrine growth inhibitor in normal cells of the epithelial lineage by inducing cell cycle arrest and apoptosis, and many human cancers escape from TGF-b1-mediated growth suppression by mutational alterations of its receptors or Smads (Markowitz et al, 1995). Unlikely normal epithelial cells, carcinoma cells produce active TGF-b1, which promotes tumor growth, migration and metastasis (Stearns et al, 1999;Zhu and Kyprianou, 2005;Lu et al, 2007;Pu et al, 2009). In prostate tumorigenesis, TGF-b1 has biphasic functions, having a growth inhibitory effect at early stages, but at later stages enhancing the malignant properties of tumors.…”

“…However, both intracellular and serum TGF-b1 levels are elevated in cancer patients and further increased in patients with metastatic carcinoma (Truong et al, 1993). Several studies have shown that prostate cancer cells are resistant to TGF-b1-induced growth inhibition, and TGF-b1 actually promotes tumor growth, migration and metastasis, indicating that TGF-b1 action is oncogenically conversed in the process of tumorigenesis (Stearns et al, 1999;Zhu and Kyprianou, 2005;Lu et al, 2007;Pu et al, 2009). We reported that TGF-b1 promotes cellular proliferation of prostate carcinomas through the activation of Ras/MAPK signaling and induction of tumor-promoting genes, such as interleukin-6, indicating that prostate cancers have a selective growth advantage by autocrine TGF-b1 production (Park et al, 2000(Park et al, , 2003.…”

Deletion ofp21/Cdkn1aconfers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model

“…20,23 The function of p53 and Rb is abrogated by SV-40 large T antigen; as a result, TRAMP male mice develop spontaneous progressive stages of PCa with time from early lesions of prostatic intraepithelial neoplasia (PIN) to late stage adenocarcinoma. 20,23 Furthermore, this PCa model has been also crossed with other genetically manipulated mice so as to generate bigenic mice, [28][29][30][31] which are employed to study the role of specific molecules in PCa progression. The changing patterns of CDKs and cyclins have been also well characterized during the progression of PCa in TRAMP model; 32 notably, we have reported the increased expression of p21 protein in TRAMP prostate with advanced stage of the disease.…”

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

“…Mutational inactivation of TGF-b signal-transduction components, such as the TGF-b type II receptor (TGFbRII) (60) or its mediators, Smad2 and Smad4, leads to defective TGF-b signaling in some cancers (17,59). Pu et al developed a transgenic adenocarcinoma of mouse prostate-based prostate cancer transgenic mouse model that harbors the dominant negative mutant TGF-b type II receptor in epithelial cells to characterize the in vivo consequences of inactivated TGF-b signaling on prostate tumor initiation and progression, and found that disruption of TGF-b signaling in vivo accelerated pathologic malignant changes in the prostate by altering the kinetics of prostate growth and inducing EMT (143). These findings indicate that TGF-b exerts its tumor suppressor functions through inhibition of cell proliferation, induction of apoptosis, and regulation of autophagy.…”