 |
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 is driven by the hypothesis that: 1) cathepsin K is a key regulator of fat cell formation and an orchestrator of the proinflammatory state in the bone marrow; and 2) cathepsin K promotes metastasis by regulating several critical factors within the bone marrow microenvironment. To validate causal role of cathepsin K in metastasis of prostate tumors we are: a) utilizing an intra-tibial cathepsin K knockout model of intraosseous tumor growth; b) developing novel homotypic and heterotypic 3D cultures from the knockout model; and c) specifically targeting macrophage- and adipocyte-derived factors and their effect on prostate tumor biology. Our short-term goal is to identify novel functions/pathways for cathepsin K in obesity, inflammation and malignancy and validate them using the in vivo models that recapitulate all stages of progression of prostate cancer. The long-term objective is to develop an in vivo tractable model of obesity/inflammation-induced prostate cancer by combining orthotopic models of prostate cancer with mouse models of inflammation and obesity. Ultimately these studies could lead to development of new therapies or novel applications of already existing drugs for prostate cancer.
 |
Figure 2. Localization of cathepsin K (red) to osteoclasts (A) and stromal cells (B) in PC3 bone tumors. |
- Additional research interests:
- Role of collagen I matrikine fragments in targeting of bone tissue by prostate and breast tumor cells. A number of studies have demonstrated, the breakdown fragments of extracellular matrix (ECM) proteins possess novel biological activities. Specifically, cathepsin K- or MMP-generated type I-collagen fragments, which were identified by our collaborator Dr. William Wu (Henry Ford Health System) stimulate expression of many proteases in human breast tumor cells and promote production of osteoclasts in cell culture. Both, the breast and the prostate tumor cells have high propensity to metastasize to the skeleton. Based on the hypothesis that collagen I fragments stimulate secretion of proinflammatory cytokines and have chemotactic properties toward breast and prostate tumor cells, we are interested in identifying receptor(s) and signaling pathways involved in this process.
- Metabolic syndrome and aggressive prostate cancer. Metabolic syndrome is described as a cluster of conditions, which serve as cardiovascular risk factor. Some components of metabolic syndrome (e.g., abdominal obesity, lipid abnormalities, insulin resistance, hypertension) have been suggested as risk predictors for prostate cancer. Metabolic syndrome has been associated with increased secretion of proinflammatory cytokines (e.g., C-reactive protein, IL-6, TNFa) and imbalance in adipokine levels (e.g., reduced levels of anti-inflammatory and anti-tumorigenic adiponectin). Adiponectin is a cathepsin K substrate and a fat hormone best known for regulation of insulin sensitivity. The full-length adiponectin exists as a trimer, hexamer, and a high molecular weight multimer complex (HMW). Adiponectin circulates in the plasma at high levels (µg/ml range) mainly in its HMW form (>80%) and its levels are significantly decreased in obesity and advanced prostate cancer. The HMW/total adiponectin and adiponectin/CRP (C-reactive protein) ratios are significantly lower in subjects with metabolic syndrome. Low levels of adiponectin have also been correlated with hypertension and arterial stiffness, a prostate cancer risk predictor in certain ethnic groups. Our research interests are to utilize human samples from patients with non-aggressive and aggressive prostate cancer, and patients representing various ethnic groups to: 1) validate the role(s) of cathepsin K in regulation of adiponectin bioactivity; 2) assess how various forms of adiponectin correlate with metabolic syndrome and prostate cancer risk.
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
Search PubMed for publications from I. Podgorski
