Differential Expression of Matrix Metalloproteinase-2 Expression in Disseminated Tumor Cells and Micrometastasis in Bone Marrow of Patients with Nonmetastatic and Metastatic Prostate Cancer: Theoretical Considerations and Clinical Implications—An Immunocytochemical Study
Matrix metalloproteinase-2 (MMP-2) is important in the dissemination and invasion of tumor cells and activates angiogenesis. We present an immunocytochemical study of MMP-2 expression in circulating prostate cells (CPCs), disseminated tumor cells (DTCs), and micrometastasis (mM) in bone marrow of men with prostate cancer. Methods and Patients. Tumor cells were identified with anti-PSA immunocytochemistry. Positive samples underwent processing with anti-MMP-2, its expression was compared with Gleason score, concordance of expression, and metastatic and nonmetastatic disease. Results. 215 men participated, CPCs were detected in 62.7%, DTCs in 62.2%, and mM in 71.4% in nonmetastatic cancer; in metastatic cancer all had CPCs, DTCs, and mM detected. All CPCs and DTCs expressed MMP-2; in mM MMP-2 expression was positively associated with increasing Gleason score. MMP-2 expression in CPCs and DTCs showed concordance. In low grade tumors, mM and surrounding stromal cells were MMP-2 negative, with variable expression in high grade tumors; in metastatic disease, both mM and stromal cells were MMP-2 positive. Conclusions. CPCs and DTCs are different from mM, with inhibition of MMP-2 expression in mM of low grade tumors. With disease progression, MMP-2 expression increases in both mM and surrounding stromal cells, with implications for the use of bisphosphonates or MMP-2 inhibitors. 1. Introduction With the increasing use of prostate specific antigen as a screening test to detect prostate cancer, the frequency of men presenting with metastatic disease has decreased [1, 2]. However, the death rate from prostate cancer has only slightly fallen [3], with metastatic disease being the commonest scenario leading to death. At least 85% of men with advanced disease will have bone metastasis [4, 5], with an increasing number of these patients believed to be metastasis-free at the time of initial treatment but who had occult micrometastasis. Furthermore, 30% to 50% of men with localized prostate cancer will develop biochemical failure with an increased PSA at 10 years. This is due to dissemination of cancer cells early in the disease and being not detected by conventional methods. Cancer cells disseminate from the original cancer, first to the neurovascular structures and then to the blood [6]. From there they pass to other tissues where they may pass through (cells in transit) or adhere to the capillary endothelium and invade, forming micrometastasis. Tumor invasion is considered to be an unregulated physiological activity, with similarities between the molecular events of
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