Integrin Biology in Prostate Cancer Skeletal Metastasis
Prostate cancer (PCa) is a significant health problem among men in the United States. In 2013, PCa is expected to be the most frequently diagnosed cancer in men and the second leading cause of cancer-related deaths within this group. Of the 28,000 estimated deaths attributable to PCa this year, all will follow the metastatic spread of the disease from the prostate to distant organs including the dura, liver, lung, and skeleton. The most frequent distant metastases formed by malignant PCa are within the skeleton. Studies of men with progressive castration-resistant PCa indicate that nearly one half of patients will develop skeletal metastases within two years; whereas, at autopsy greater than 80% of all men who die of PCa will have metastatic disease within the bone, specifically in the trabecular bone of the pelvis, femur, and vertebral bodies. Outgrowth of tumors within the bone is quite debilitating resulting in severe pain, fracture, nerve compression/paralysis, and death. Thus to improve the quality of life for PCa patients, a better understanding of the biology of skeletal metastases is needed.
The goal of my research program is to define the mechanism through which PCa cells preferentially metastasize to the skeleton. Recent data suggest that the colonization of the skeleton is mediated in part by collagen type I, the most abundant protein within the bone. We have shown that enhanced binding to collagen I through increased expression of integrin a2b1 stimulated in vitro invasion and promoted the growth of PCa cells within the bone. We have further shown that the invasive phenotype of collagen I-binding PCa cells is mediated in part by the a2b1-dependent activation of RhoC GTPase. The selective knock-down of a2b1 integrin was found to reduce both RhoC activity and the experimental metastasis of PCa cells to the bone confirming that a2b1 integrin promotes PCa skeletal metastasis. Current studies are focused on identifying the molecular mechanism of a2b1-mediated RhoC activation as well as defining the role of collagen I/a2b1 integrin in the transition from cellular dormancy to metastatic growth within disseminated PCa cells.
Ph. D., The University of Texas Health Science Center at Houston, 2001