Matrix Metalloproteinase-14: A Novel Marker of Tumor Progression and Invasion in Prostate Cancer
Golrokh Javid, Raid Aljumaily, Rajani Kaimal, Sheida Sharifi, Anika Agarwal. Tufts Medical Center, Boston, MA
Background: Emerging evidence has shown that matrix metalloproteinase-14 (MMP14) plays a pivotal role in prostate cancer bone metastases, the leading cause of morbidity/mortality in affected patients. MMP14 is known as one of the critical proteases involved in cell migration which degrades extracellular matrix to furnish a path for cells to migrate, sheds cell surface molecules, and activates extracellular signal-regulated protein kinase. We hypothesized that prostate cancer cells with higher expression of MMP14 have a more aggressive phenotype and tendency to migrate to the bone. The goal of this study is to evaluate the role of MMP14 monoclonal antibody in blocking migration and invasion of prostate cancer cell lines (PC-3 and DU-145) in vitro, and to further evaluate MMP14 expression pattern in vivo to assess if higher expression of MMP14 is associated with an invasive phenotype in human prostatic tissue.
Design: In vitro: Prostate cancer cell lines PC-3 and DU-145 were used. Chemotactic migration and chemoinvasion were evaluated using transwell apparatus following selective blockade of MMP14.
In vivo: Formalin Fixed Paraffin Embedded human tissues were retrieved, including 20 cases of prostate adenocarcinoma (PAC) with either perineural, lymphovascular or extraprostatic invasion, and 20 cases of benign prostatic hyperplasia (BPH; control). Immunohistochemistry was performed for MMP14. Intensity, using a 4-grade scale, and pattern (nuclear/cytoplasmic and diffuse/focal) of MMP14 staining were analyzed and compared in malignant epithelial cells, benign epithelial cells (BEC) adjacent to the tumor, and BEC in the BPH.
Results: In vitro: Monoclonal MMP14 antibody significantly decreased the invasion of prostate cancer cell lines through reconstituted basement membrane compared to controls.
In vivo: The PAC (mean age: 60 yrs) and the BPH groups (mean age: 64 yrs) each consisted of 20 patients. PAC cases showed diffuse 2+ to 3+ nuclear and cytoplasmic MMP14 staining (80%) in contrast to BEC in BPH that showed 0 to +1 focal cytoplasmic staining (p<.0001). The intensity of staining in the BEC adjacent to invasive tumor cells of PAC group was also focal, and significantly lower than the invasive cells (p<.0001).
Conclusions: Our in vitro and in vivo findings are significant and help understand the role of MMP14 as a potential biomarker of disease progression and invasion in prostate cancer. Moreover, the ability of the MMP14 monoclonal antibody in blocking tumor migration and invasion, suggests that MMP14 could serve both as a disease biomarker and also as a therapeutic target for PAC.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 108, Tuesday Afternoon