Abstract
The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.
Highlights
Prostate cancer (PCa) is the leading cancer diagnosed and the second cause of cancer related death in American men
We previously reported an engineered bivalent TGF-β receptor trap protein known as betaglycan endoglin domain (BGE)-RII and demonstrated that it had improved antagonistic potency against all three TGF-β isoforms compared to its two component binding domains, the N-terminal TGF-β binding endoglin-like domain of the TGF-β co-receptor betaglycan (BGE) and the TGF-β type II receptor extracellular domain (RII) [21]
Instead of causing cell cycle arrest and/or apoptosis, TGF-β induces epithelial to mesenchymal transition (EMT), a process that facilitates migration, invasion and metastasis [42]
Summary
Prostate cancer (PCa) is the leading cancer diagnosed and the second cause of cancer related death in American men. Transforming growth factor beta (TGF-β) isoforms, TGF-β1, β2, and β3, are small (25 kDa) homodimeric signaling proteins. They are secreted in a latent form and are activated by multiple mechanisms, including integrin binding and proteolysis [2]. They form a complex with the TGF-β type I and type II receptors (TβRI and TβRII) for signal transduction, in which TβRII phosphorylates and activates TβRI [3]. The phospho-TβRI phosphorylates intracellular Smad and Smad, which form a complex with the common-mediator Smad, Smad, to regulate gene expression [4]
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