Circulating angiogenic cells in metastatic prostate cancer: assessment of the bone marrow vascular and peripheral blood vascular compartments Free

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Background: Circulating vascular cells in prostate cancer patients may be derived from multiple anatomic compartments, including primary tumors, soft tissue metastases, and the bone marrow. While the functional role of circulating endothelial cells (CEC) is unknown in patients with metastatic prostate cancer, preliminary studies have found evidence of elevated CEC levels, compared to healthy controls. One source of such cells is the bone marrow (BM), subject to damage by (1) androgen deprivation, (2) cytotoxic chemotherapy, and (3) tumor infiltration. We have previously demonstrated dramatic short term fluctuations in the bone marrow vascular structure of mice following cytotoxic chemotherapy. We are currently investigating the impact of androgen deprivation on BM vascular structure in a pre-clinical model, and, in patients, we are measuring the levels of CEC. In this study, CEC are defined by the immunophenotype CD146⁺CD105⁺CD45^-. For hormone refractory prostate cancer patients, it is hypothesized that varying levels of CEC will correlate with distinct clinical features, such as biochemical status, sites of disease, primary tumor histology, and/or modality of primary therapy. Methods: Pre-clinical studies have begun to delineate the ability of androgens to modulate the kinetics of BM vascular regression and recovery following cytotoxic chemotherapy in adult male mice. BM vascular structure is being examined serially at intervals after castration followed by high-dose cytotoxic therapy. Additionally, prospective clinical correlative studies of CEC levels have been initiated with peripheral blood samples obtained as part of phase I/II clinical trials in metastatic prostate cancer. CEC are enumerated using a semi-automated system designed for the clinical laboratory setting (Immunicon) and employs an antibody-conjugated magnetic bead separation device and an automated microscope. Results: Histologic studies of pre- and post-treatment mouse BM demonstrated rapid structural changes in the vasculature. Control assays using whole peripheral blood from healthy controls spiked with human endothelial cells have demonstrated the detection system to be sensitive for as few as ~1.1 CEC/ml whole blood. The range of CEC in castrate metastatic prostate cancer patients to date is 3.5 - 59.0/ml blood in a pilot cohort. Conclusions: Assessment of CD146⁺CD105⁺CD45^- CEC in castrate metastatic prostate cancer patients is feasible, using a high-throughput system. Determination of CEC levels may enable subclassification of advanced prostate cancer patients. BM may represent an important source of CEC.