Prostate cancer and bone: The impact of skeletal -specific microenvironmental factors in tumor localization and growth.
Schneider, Abraham
2005
Abstract
Bone metastasis is the most devastating and untreatable complication associated with prostate cancer. Despite recent progress in diagnosis and management, it is still unclear why tumor cells preferentially disseminate and grow in the skeleton, inducing the formation of aberrant bone lesions. Understanding the basic mechanisms of bone metastasis has been hampered by the lack of suitable <italic>in vivo</italic> models to test hypotheses. An ectopic bone model, generated by the differentiation of bone marrow stromal cells transplanted into immunocompromised mice was utilized to determine whether ectopic ossicles recapitulate normal bone remodeling in response to parathyroid hormone (PTH). PTH, a potent stimulator of bone turnover, increased the number of active osteoclasts as well as trabecular bone mass and marrow cellularity following the administration of catabolic or anabolic doses, respectively. Because of its functional similarity to native bone, the ectopic ossicle model offers a versatile approach to study bone biology in health and disease. Especially, it provides a promising cell transplantation strategy to elucidate basic mechanisms in bone metastatic lesions relative to tumor cell-bone interactions. Bone metastases are often found in sites containing increased marrow cellularity and active bone turnover. Differences in these factors may be crucial to facilitate skeletal tumor localization and growth. PTH was administered to stimulate bone turnover in immunodeficient mice one week before and after intracardiac inoculation of luciferase-expressing PC-3 cells. Five weeks following inoculation, bioluminescence imaging analysis demonstrated a significant increase in skeletal tumor foci in PTH-treated adult mice versus controls. Serum bone turnover markers, marrow cell proliferation as well as skeletal tumor localization were markedly reduced when zoledronic acid was administered concurrently with PTH. Further, <italic>in vitro</italic> studies demonstrated that elevated concentrations of extracellular calcium, a major inorganic component of bone released following tumor-mediated osteolysis, increased PC-3 cell proliferation via the calcium-sensing receptor, in part by activating the PI3K/Akt pathway and maintaining elevated cyclin D1 levels. This dissertation underscores the impact of a congenial microenvironment in facilitating prostate cancer skeletal localization and growth. Furthermore, it identifies and validates key skeletal-specific factors as potential therapeutic targets to control prostate cancer skeletal metastases.Subjects
Bone Regeneration Growth Impact Microenvironmental Factors Prostate Cancer Skeletal-specific Tumor Localization
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