Abstract 1532: The identification of osteoblastic and osteolytic factors in prostate cancer bone metastases
Authors: Zhang Xiaotun , Larson Sandy , Dumpit Ruth , Coleman Ilsa , Lakely Bryce , Roudier Martine , Higano Celestia , True Lawrence D. , Lange Paul H. , Nelson Peter S. , Corey Eva , Vessella Robert L. , Morrissey Colm 
Published: August 2012

Abstract
Prostate Cancer (PCa) metastasizes to the bone in approximately 90% of patients who die of PCa. Growth of tumor cells in the bone can lead to replacement of bone marrow, spinal cord compression, severe bone pain, cachexia and death. The bone response to a metastasis can manifest as a spectrum of osteoblastic to osteoblastic/osteolytic (mixed) or osteolytic responses in the same patient at different biopsy sites. A number of proteins have been proposed to promote the osteoblastic and osteolytic responses in PCa bone metastasis. Our objective was to determine whether known bone forming and degrading factors are associated with the osteoblastic or osteolytic response in pre-clinical models and clinical specimens of PCa bone metastasis. Additionally, we wanted to identify novel proteins that may be associated with the osteoblastic and osteolytic response in PCa bone metastases. Using specimens obtained at rapid autopsy at the University of Washington, we compared the gene expression profile of osteoblastic and osteolytic metastases (n=14) from 13 patients and validated our findings by qRT-PCR. We also interrogated the same factors at the protein level in 18 osteoblastic and 18 osteolytic PCa bone metastases from 27 patients by immunohistochemistry (IHC). Additionally, we are currently interrogating the levels of these factors in 6 novel LuCaP xenograft models of PCa that promote an osteoblastic response and 4 that promote an osteolytic response in the tibia of immune compromised mice by IHC. Using gene expression arrays, validated by qRTPCR, we identified a putative osteoblastic factor EMID1 (p=0.01) and two putative osteolytic factors, MMP12 (p=0.03) and sFRP1 (p=0.02). By IHC, MMP12 expression approached significance (p=0.07), whereas sFRP1 was significantly higher in the osteolytic samples (p=0.02). Interestingly, we did not observed significant differences in transcript levels between osteoblastic and osteolytic metastases for a number of proposed osteoblastic and osteolytic factors including BMP2 and 7, tachykinin 1, endothelin 1, osteoprotegerin, and sclerostin. Furthermore, none of the proposed osteoblastic and osteolytic factors we interrogated by IHC showed a significant difference in protein expression between osteoblastic and osteolytic PCa bone metastases. This is the first detailed analysis of PCa osteoblastic and osteolytic factors in human specimens and animal models of PCa in the bone. Our data suggest that many of the factors important in bone remodeling may not be central to the bone response in PCa bone metastases. Additionally we have identified three factors that may have a role in bone remodeling in PCa bone metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1532. doi:1538-7445.AM2012-1532