Transforming growth factor-b (TGF-b has a dual role in tumorigenesis, initially functioning as a tumor suppressor and subsequently as a tumor promoter. A fundamental gap in knowledge exists in terms of mechanisms for the dichotomous function of TGF-b. The type III TGF-b receptor (TbRIII) has an emerging yet poorly understood role in regulating TGF-b signaling and carcinogenesis. We have establishing that TbRIII specifically inhibits cancer cell migration and invasion, in part by undergoing ectodomain shedding, releasing soluble TbRIII (sTbRIII). To investigate the mechanism of TbRIII function, the following hypothesis is proposed: Cell surface TbRIII decreases the migration of ovarian surface epithelial cells and ovarian cancer cells by activating Cdc42, disrupting the actin cytoskeleton, focal adhesion formation, polarity and inhibiting directional migration, while sTbRIII, generated through MMP-mediated ectodomain shedding, functions to inhibit TGF-b signaling and MMP production through a novel Smad1 pathway and TbRIII activates Cdc42 to inhibit the invasiveness of breast and ovarian cancer cells. This hypothesis will be addressed by four Specific Aims.
Specific Aim 1 : The mechanism by which TbRIII undergoes ectodomain shedding to produce sTbRIII will be established by examining the proteases involved, defining the site(s) of cleavage and how the process is regulated.
Specific Aim 2 : The mechanism by which TbRIII inhibits migration of ovarian surface epithelial cells and ovarian cancer cells will be established by examining the functional elements required for TbRIII function, and the effect of TbRIII-mediated activation of CDC42 pathways on polarity, directed migration, the actin cytoskeleton and focal complex formation.
Specific Aim 3 : The mechanism by which TbRIII inhibits invasion of breast and ovarian cancer cells will be established by examining the functional elements required for TbRIII function, the effect of sTbRIII on TGF-b cell surface binding, TGF-b signaling through Smad1 and MMP production and the effect of TbRIII-mediated activation of CDC42 pathways on invasion.
Specific Aim 4 : The effect of blocking TbRIII shedding and sTbRIII production, directly decreasing cell surface TbRIII and sTbRIII expression or expressing TbRIII and/or sTbRIII on both breast and ovarian cancer cell functions including proliferation, apoptosis, invasion and angiogenesis in vitro and tumor formation and metastasis in vivo will be explored to determine whether cell surface TbRIII and sTbRIII function in concert to decrease breast and ovarian cancer progression. These studies will define the mechanism by which TbRIII inhibits breast and ovarian cancer cell migration and invasion, including the role of ectodomain shedding, define the biological implications of ectodomain shedding of TbRIII in the context of human breast and ovarian cancers, and aid in the design of specific interventions for the prevention and treatment of human breast and ovarian cancers and other human cancers in which TbRIII has a defined role.
We have demonstrated that a cell surface receptor for the transforming growth factor-2 (TGF-b), the type III TGF-b receptor (TbRIII), is able to suppress cancer progression in a broad spectrum of human cancers, including cancers of the breast, lung, ovary, pancreas and prostate, by decreasing the ability of the cancer cells to migrate, invade and spread to distant sites. Regulating migration and invasion are also essential processes during embryonic development, tissue repair and in the immune response and have prominent roles in inflammatory and vascular diseases. Thus, these studies where we will investigate mechanisms by which TbRIII inhibits migration, invasion and metastatic spread are important to perform and relevant to public health as these mechanistic insights will define the biological functions of TbRIII in the context of human breast and ovarian cancers, increase understanding of the role of TGF-b signaling and of TbRIII in regulating migration and invasion and aid in targeting the TGF-b signaling pathway for the treatment of these cancers and other diseases in which migration and invasion or the TGF-b signaling pathway has a prominent role.
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