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Izabela Podgorski, Ph.D. |
RESEARCH INTERESTS:
Recent clinical data suggest that approximately 90% of patients who die from advanced refractory prostate cancer have clinical evidence of skeletal metastasis. Obesity is a major contributor to development of aggressive prostate cancer, with higher recurrence and higher mortality rates. With obesity and aging, there is a shift in bone marrow composition favoring the formation of fat cells (adipocytes). Adipocytes secrete endocrine and paracrine factors that strongly influence neighboring as well as distant cells. Marrow adipocytes also secrete inflammatory cytokines capable of recruiting osteoclasts and contributing to dysregulated bone remodeling. Recent studies suggest that accelerated bone remodeling may be responsible for homing of tumor cells to the bone. Cathepsin K is an osteolytic enzyme involved in bone resorption, and currently a pharmaceutical industry target for treatment of osteoporosis. This protease has an established role in inflammation and several malignancies, and is a newly identified factor important for adipogenesis. Cathepsin K interacts with several proteins within the bone marrow microenvironment, and has recently been implicated in mobilization of hematopoietic progenitor cells, a putative process in homing of tumor cells to specific organs.
Figure 1. Proposed model for the role of cathepsin K in obesity-induced bone resorption and homing of prostate tumors to the bone (From Podgorski et al, Biochem Soc. Trans, 2007
Our main research interests are to: identify molecular mechanisms underlying the association between obesity, inflammation and prostate cancer. Our current work focuses on cathepsin K as a regulator of fat cell formation, an orchestrator of the proinflammatory state in the bone marrow, and a major player in skeletal metastasis. For our studies, we are utilizing an in vivo knockout model of bone metastasis and in vitro, mesenchymal stem cell-based homotypic and heterotypic models of adipogenesis, osteogenesis and adipocyte-tumor cell interactions. In addition to adipocytes and osteoblasts, we are also specifically targeting macrophage-derived factors and their effect on prostate tumor biology.
Our long-term objective is to develop an in vivo tractable model of obesity/inflammation-induced prostate cancer and use it as a tool for development of new therapies or novel applications of already existing drugs for prostate cancer.
INVESTIGATING NOVEL FUNCIONS/ PATHWAYS FOR CATHEPSIN K IN BONE METASTASIS,
INFLAMMATION AND FAT CELL FORMATION
Our additional research interests involve metabolic syndrome/inflammation-, insulin resistance- and oxidative stress-related factors that differentially influence prostate cancer aggressiveness in African American and European American men. Using human blood samples from prostate cancer patients, we are exploring biochemical and genetic factors associated with racial differences in prostate cancer incidence, progression and risk of recurrence.
Current Lab Personnel:
Mackenzie Herroon, M.S. – Research Assistant; mherroon@med.wayne.edu
Debbie Rudy, B.S. – Research Assistant; drudy@med.wayne.edu
SELECTED RECENT PUBLICATIONS
- Podgorski, I. and Sloane, B.F.: Cathepsin B and its role(s) in cancer progression. In: Proteases and the Regulation of Biological Processes. (J. Saklatvala, H. Nagase and G. Salvesen, eds.), Biochemical Society Symposium 70, Portland Press, London, pp. 263-276, 2003. PMID: 14587299
- Podgorski, I., Linebaugh, B.E., Sameni, M., Jedeszko, C., Bhagat, S., Cher, M.L. and Sloane, B.F.: Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer. Neoplasia 7: 207-223, 2005. PMID: 15799821
- Sloane, B.F., Sameni, M., Podgorski, I., Cavallo-Medved, D. and Moin, K.: Functional imaging of tumor proteolysis. Annu. Rev. Pharmacol. Toxicol, 46, 301-315, 2006. PMID: 16402907
- Podgorski, I. And Sloane, B.F. Loss of caspase-8 in tumor cells: mechanism to overcome integrin-mediated death? Mol Interv. 6(3), 132-136, 2006. PMID: 16809473
- Podgorski, I, Linebaugh, B.E, and Sloane, B.F. Cathepsin K in the Bone Microenvironment: Link Between Obesity and Prostate Cancer? Biochemical Society Transactions, 35(4), 701-704, 2007. PMID: 17635127
- Jedeszko, C., Victor, B.C., Podgorski, I. and Sloane, B.F. Fibroblast Hepatocyte Growth Factor Promotes Invasion of Human Mammary Ductal Carcinoma in Situ. Cancer Res 69 (23), December, 2009.
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