We have recently contributed to major achievements in modeling human prostate cancer in mice. Global assessment of molecular changes in these models have led to identification of key gene functions implicated in human prostate cancer and its metastases. Two such functions are the focus of this proposal. These molecules, both secretory and commonly referred to as bone matrix proteins, are: osteopontin (OPN), an RGD-containing glycosylated phosphoprotein, and osteogenic protein-1 (OP-1 or BMP-7), a member of the TGF-p superfamily. Since prostate cancer has the propensity to metastasize to bone and to induce bone lesions, and both of these proteins are believed to be involved, in osteoblast differentiation and bone formation, these molecules constitute an important, but yet an understudied area of research in the biology of prostate cancer. In preliminary experiments we find that OPN expression, prominent in prostatic preneoplastic lesions of a mouse model, continues to increase with progression to invasive adenocarcinoma, and cells overexpressing OPN are enriched in the metastatic deposits. Additional data collected to date indicate that OPN upregulation may be a factor in proliferation, motility, invasion, and most remarkably in the ability of the human prostate cancer cells to intravasate blood vessels. We find that BMP-7 expression continues to increase with the growth of the prostate cancer in our mouse model, it can modulate growth, motility and invasion properties of human prostatic epithelial cells, and it can induce epithelial-mesenchymal transition to a prostate cancer cell line. We implicate BMP receptor signaling differences with the observed differential biological responses induced. The stated goals of this application are two-fold. First to refine our metastatic prostate cancer model by incorporating the capability of either to monitor the tumor growth and site-specific metastases by in vivo bioluminescense, or to isolate cancer cells from primary tumor and organspecific metastases. Second is to define the molecular/cellular parameters by which OPN or BMP-7 may positively influence prostate cancer progression and metastases. A series of interconnected and parallel studies using the mouse model and cancer cells derived from it, human prostate cancer cell lines, and osteoblasts and precursors are outlined to obtain insight into how OPN and BMP-7 may contribute to prostate cancer progression and to the mechanism of prostate cancer-mediated osteogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA113392-05S1
Application #
8065265
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mohla, Suresh
Project Start
2005-07-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$32,434
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Adisetiyo, Helty; Liang, Mengmeng; Liao, Chun-Peng et al. (2013) Loss of survivin in the prostate epithelium impedes carcinogenesis in a mouse model of prostate adenocarcinoma. PLoS One 8:e69484
Pham, Linda Kim; Liang, Mengmeng; Adisetiyo, Helty A et al. (2013) Contextual effect of repression of bone morphogenetic protein activity in prostate cancer. Endocr Relat Cancer 20:861-74
Jeong, Joseph H; Bhatia, Ayesha; Toth, Zsolt et al. (2011) TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth. PLoS One 6:e16205
Lim, Minyoung; Chuong, Cheng-Ming; Roy-Burman, Pradip (2011) PI3K, Erk signaling in BMP7-induced epithelial-mesenchymal transition (EMT) of PC-3 prostate cancer cells in 2- and 3-dimensional cultures. Horm Cancer 2:298-309
Liao, Chun-Peng; Liang, Mengmeng; Cohen, Michael B et al. (2010) Mouse prostate cancer cell lines established from primary and postcastration recurrent tumors. Horm Cancer 1:44-54
Liao, Chun-Peng; Adisetiyo, Helty; Liang, Mengmeng et al. (2010) Cancer stem cells and microenvironment in prostate cancer progression. Horm Cancer 1:297-305
Xu, Tong; Xu, Yucheng; Liao, Chun-Peng et al. (2010) Reprogramming murine telomerase rapidly inhibits the growth of mouse cancer cells in vitro and in vivo. Mol Cancer Ther 9:438-49
Liao, Chun-Peng; Adisetiyo, Helty; Liang, Mengmeng et al. (2010) Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer Res 70:7294-303
Jiang, M; Fernandez, S; Jerome, W G et al. (2010) Disruption of PPARgamma signaling results in mouse prostatic intraepithelial neoplasia involving active autophagy. Cell Death Differ 17:469-81

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