Abstract: The long-term objective of this proposal is to gain insight into mechanism of prostate cancer metastases to bone and attendant pathology of osteosclerosis. What is the cellular and molecular basis of osteotropism of metastatic prostate cancer in humans? The predominant site of prostate cancer is bone. However, unlike the osteolytic lesions of breast cancer, prostate cancer causes osteoblastic osteosclerosis which leads ultimately to morbidity and mortality. During the osteoscleorotic phase of prostate cancer metastases to bone there is increased bone formation. It is proposed to investigate the hypothesis that bone matrix is the 'soil' that promotes the 'seeds' of prostate carcinoma. Recent work has identified bone induction and stimulation by a family of bone morphogenetic proteins (BMPs). We have documented BMP 4 and BMP 7 expression in mouse prostate and BMP 6 in human prostate cells. It is plausible that metastatic human prostate cells produce BMPs which act in an autocrine- paracrine loop to stimulate bone formation and osteosclerosis based on their known motogenic, mitogenic and osteogenic actions. The specific aims of this hypothesis-driven proposal are (1) To investigate the expression of BMP antagonists and BMP receptors prostate cancer cell lines. (2) Generate clones of LNCaP cells with over-expression of BMP 6 and over-expression of BMP antagonist, DAN by stable plasmid transfections. Test the hypothesis DAN, a BMP antagonist binds to BMP 6. (3) Investigate the hypothesis that over-expression of BMP 6 leads to increased metastases to bone in a SCID mouse. The accrued knowledge of BMP signaling pathways including receptors and native antagonists, will help aid in the design of potential antagonists to block BMP signaling and reduce pain and pathologic fractures of bone in prostate cancer metastases.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 12 Dec 2001-11 Dec 2002 |
| Pages: |
32 |
| Report Date: |
JAN 2003 |
| Contract Number: |
DAMD17-02-1-0021 |
| Report Number: |
A987614 |
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