Prostate cancer (PC) bone metastases are characterized by their ability to induce osteoblastic lesions and local bone formation. The pathophysiology of this skeletal response is not currently known. Many reports have recently shown that osteoblastic metastatic PC cells are osteomimetic and capable of expressing genes and proteins which are known to be expressed by osteoblasts. The Notch signaling pathway plays a pivotal role in determining cell fate. It has been shown that osteoblast differentiation is dependent upon Notch1 activation by DIl1 (Notch ligand) and we have previously demonstrated that Notch1 is responsible for the osteomimetic properties of PC cell lines. Therefore, we hypothesize that prostate carcinoma bone metastases express functional Notch receptors, which are activated in the bone environment resulting in a transformation of prostate carcinoma cells into osteoblast like cells. To test this hypothesis, we will use human PC cell lines which are derived from osteoblastic, osteolytic and mixed metastases, human mesenchymal stem cells, and samples from human prostate bone metastases.
The aims of this study are: (1) Characterize the expression of Notch receptors and Notch ligands in metastatic prostate carcinoma. RNA and protein expression will be examined in PC cell lines and human clinical samples. (2) Characterize the molecular mechanisms responsible for osteoblastic transformation of metastatic prostate carcinoma. Western blot and gel shift analysis and transactivation studies will be utilized to elucidate the mechanism. (3) Determine the role of Notch signaling in prostate cancer bone metastasis. Notch activity will be inhibited pharmacologically. The fate of PC cells will be examined in vitro and in a mouse model. Findings from these studies will provide the first documentation of a novel mechanism to explain the ability of prostate cancer's skeletal metastases to induce osteoblastic lesions. A basis will thereby be provided for the development of a new target for drug design and therapeutic intervention to combat the debilitating condition of PC metastases to bone.
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