Prostate tumor metastasis characteristically occurs in bone and often results in the poor prognosis of patients. Unfortunately, there are no treatments that specifically target the molecular pathogenesis of bone metastasis. Recent studies have indicated that prostate tumor cells exhibit an enhanced avidity for bone marrow endothelium (BMEC) compared with adhesion to blood vessel linings in other tissues. Our laboratory has shown that initial adhesive interactions between bone-metastatic prostate tumor cells and BMEC is mediated by endothelial (E)-selectin. We have identified a candidate prostate tumor cell E-selectin ligand known as P-selectin glycoprotein ligand-1 (PSGL-1). Remarkably, expression analysis of PSGL-1 on tissue micro-arrays (TMA) of normal prostate epithelium and of localized and metastatic prostate tumor tissue has revealed that PSGL-1 is almost exclusively found on metastatic prostate tumor cells, including tumor cells in bone. We hypothesize that PSGL-1 facilitates prostate tumor metastasis, including the bone tropic behavior of prostate cancer. The objective of studies outlined in this proposal is to elucidate the molecular pathogenesis of prostate tumor metastasis and identify tumor cell receptors that promote metastatic behavior and/or possess structural motif(s) for targeting of novel anti-cancer therapies.
The specific aims are: 1) To analyze the glycobiological regulation of E-selectin ligand and PSGL-1 on metastatic prostate tumor cells and 2) To investigate the functional role of E-selectin-binding PSGL-1 in prostate tumor metastasis. Experimentation will include innovative Western blotting, blot rolling and cell adhesion assays as well as in vivo rolling assays of PSGL-1 + and - metastatic prostate tumor cells. We will employ a hu-bone-NOD-SCID mouse model to explore the role of PSGL-1 in human prostate tumor progression and metastasis. PSGL-1 + or - human metastatic prostate tumor cells will be analyzed for their capacity to home into human bone xenografts. TRAMP mice, which develop spontaneous prostate adenocarcinoma and distant metastases, will be crossed into PSGL-1 null mice to directly test the role of PSGL-1 in prostate tumor progression and metastasis, in vivo. Results from these analyses will offer new insights into the molecular pathogenesis of prostate tumor metastasis and may provide rationale for development of new therapies targeting homing receptors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118124-05
Application #
8007391
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Snyderwine, Elizabeth G
Project Start
2007-04-05
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$274,238
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Barthel, Steven R; Hays, Danielle L; Yazawa, Erika M et al. (2013) Definition of molecular determinants of prostate cancer cell bone extravasation. Cancer Res 73:942-52
Cedeno-Laurent, Filiberto; Opperman, Matthew J; Barthel, Steven R et al. (2012) Metabolic inhibition of galectin-1-binding carbohydrates accentuates antitumor immunity. J Invest Dermatol 132:410-20
Cedeno-Laurent, Filiberto; Opperman, Matthew; Barthel, Steven R et al. (2012) Galectin-1 triggers an immunoregulatory signature in Th cells functionally defined by IL-10 expression. J Immunol 188:3127-37
Cedeno-Laurent, Filiberto; Watanabe, Rei; Teague, Jessica E et al. (2012) Galectin-1 inhibits the viability, proliferation, and Th1 cytokine production of nonmalignant T cells in patients with leukemic cutaneous T-cell lymphoma. Blood 119:3534-8
Cedeno-Laurent, Filiberto; Dimitroff, Charles J (2012) Galectin-1 research in T cell immunity: past, present and future. Clin Immunol 142:107-16
Barthel, Steven R; Antonopoulos, Aristotelis; Cedeno-Laurent, Filiberto et al. (2011) Peracetylated 4-fluoro-glucosamine reduces the content and repertoire of N- and O-glycans without direct incorporation. J Biol Chem 286:21717-31
Cedeno-Laurent, Filiberto; Barthel, Steven R; Opperman, Matthew J et al. (2010) Development of a nascent galectin-1 chimeric molecule for studying the role of leukocyte galectin-1 ligands and immune disease modulation. J Immunol 185:4659-72
Barthel, Steven R; Wiese, Georg K; Cho, Jaehyung et al. (2009) Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking. Proc Natl Acad Sci U S A 106:19491-6
Wiese, Georg; Barthel, Steven R; Dimitroff, Charles J (2009) Analysis of physiologic E-selectin-mediated leukocyte rolling on microvascular endothelium. J Vis Exp :
Barthel, Steven R; Gavino, Jacyln D; Wiese, Georg K et al. (2008) Analysis of glycosyltransferase expression in metastatic prostate cancer cells capable of rolling activity on microvascular endothelial (E)-selectin. Glycobiology 18:806-17

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