Integrins comprise a large family of cell surface receptors with critical roles in cell adhesion, and signal transduction. These properties are exploited in cancer, affecting the spectrum of growth, proliferation. Invasion and metastatic potential of human tumor cells. Because of these broad signaling functions, and easy accessibility at the cell surface, integrins are attractive therapeutic targets in cancer, but their molecular requirements in tumorigenesis are not completely understood. Recent studies have uncovered a novel pathway of integrin signaling critically exploited for prostate cancer progression. We found that integrin avB6 is prominently expressed in prostate cancer, but not in normal prostate, in vivo. In turn. avp6 orchestrates a broad signaling pathway in the prostatic epithelium, triggering androgen receptor (AR) activation, upregulating the expression of survivin, a master switch of cell proliferation and cell survival in cancer, and promoting osteolytic lesions in the bone microenvironment. This pathway results in increased tumor cell invasion, and enhanced metastatic dissemination, in vivo. Therefore, the hypothesis that avp6 orchestrates a novel signaling network of prostate cancer progression can be formulated, and will constitute the focus of the present application. In the first specific aim, experiments will be carried out to elucidate the mechanistic requirements and functional implications of avp6 upregulation of survivin in prostate cancer, with respect to transcriptional/post-transcriptlonal responses, modulation of mitochondrial apoptosis, and control of cell cycle checkpoints in response to ionizing irradiation. The second specific aim will investigate whether the signaling circuits mediated by avp6 and other integrins regulate an AR-Runx2 transcriptional complex in bone remodeling during metastatic prostate cancer growth. In the third specific aim, we will target the avp6 pathway with a novel function-blocking monoclonal antibody 6.SG9 in preclinical molecular and genetic models of localized and metastatic prostate cancer, in vivo. The overall application combines mechanistic evaluation of integrin-modulation of tumor progression with state-of the-art studies of developmental therapeutics in advanced prostate cancer. The results will open concrete opportunities for novel molecular molecular therapy of patients with advanced prostate cancer.
We have uncovered a novel pathway of prostate cancer progression centered on the signaling properties of avB6 integrin. Therapeutic targeting of this pathway using molecular and genetic disease models that approximate the human disease, combined with mechanistic dissection of its molecular requirements, may open concrete new prospects for the rational treatment of patients with advanced and metastatic prostate cancer.
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