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

Nigel P Murray,Leonardo Badínez,Pablo Tapia,Eduardo Reyes,Nelson Orellana

doi:10.1155/2012/259351

Abstract

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.

Highlights

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]
We present an immunocytochemical study of Matrix metalloproteinase-2 (MMP-2) expression in circulating prostate cells (CPCs), disseminated tumor cells (DTCs), and micrometastasis in bone marrow of men with prostate cancer
If this hypothesis is correct, circulating tumor cells should express MMP-2 whether they are circulating in blood or the bone marrow, and MMP-2 expression would permit the invasion of the endostium and facilitate the formation of micrometastasis

Summary

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]. As the reports indicate, increased MMP-2 expression in the primary tumor is associated with a worse prognosis, one explication could be that cells expressing MMP-2 disseminate early to distant tissues, are not affected by loco-regional treatments, and as a consequence are able to develop into metastasis. If this hypothesis is correct, circulating tumor cells should express MMP-2 whether they are circulating in blood or the bone marrow, and MMP-2 expression would permit the invasion of the endostium and facilitate the formation of micrometastasis. These data prompted us to investigate the expression of MMP-2 in circulating prostate cells in blood and bone marrow, and in the micrometastasis in bone marrow fragments in a population of patients with prostate cancer, after radical prostatectomy, both in patients bone scan negative and positive

Methods and Patients

Results

Discussion