Prognostic Significance of Matrix Metalloproteinase 2 and Tissue Inhibitor of Metalloproteinase 2 Expression in Prostate Cancer

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading the structural support network for normal and malignant cells, promoting neoplastic cell invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) maintain connective tissue integrity by modulating MMP activity. Formalin-fixed paraffin-embedded tissue sections from 138 prostatic adenocarcinomas (PACs) were immunostained by a combined automated/manual method using monoclonal antibodies against MMP2 and TIMP2. Immunoreactivity was semiquantitatively scored based on stain intensity and distribution, and results were correlated with Gleason grade, pathologic stage, ploidy status, and disease recurrence. One hundred five of 138 (76%) and 113/138 (82%) PACs expressed MMP2 and TIMP2, respectively. Co-expression was observed in 94/138 (68%) of PACs (P ‫؍‬ .01), correlated with advanced tumor stage (P ‫؍‬ .05), and tended to be associated with disease recurrent cases (P ‫؍‬ .07). TIMP2 expression individually correlated with advanced tumor stage (P ‫؍‬ .04) and reached near significance with disease recurrence (P ‫؍‬ .06). MMP2 expression was also more frequent in recurrent PACs, although this value did not reach statistical significance (P ‫؍‬ .07). However, on multivariate analysis, only pathologic stage (P ‫؍‬ .009) and ploidy status (P ‫؍‬ .03) independently predicted disease recurrence. In conclusion, MMP2 and TIMP2 are co-expressed in a majority of PACs and correlate with prognostic variables. Interestingly, contrary to the previously documented anti-tumor effects of TIMPs, TIMP2 expression appears to have a tumorpromoting role in PACs and warrants further investigation. KEY WORDS: Immunohistochemistry, MMP, Prognosis, Prostate cancer, TIMP. Mod Pathol 2003;16(3):198 -205Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, degrade the basement membrane and extracellular matrix, facilitating cell migration, tumor invasion, and metastasis (1-5). There are at least 20 human MMPs, divided into the collagenases, gelatinases, stromelysins, and membrane-type MMPs (MT-MMPs; 1-5). Tissue inhibitors of metalloproteinases (TIMPs) are the major endogenous regulators of MMPs and consist of four homologous members (TIMP1-4; 6 -8). TIMPs are multifunctional proteins that inhibit cell invasion in vitro and tumorigenesis and metastasis in vivo (6). Although each TIMP appears capable of inhibiting several MMPs, these proteins exhibit preferential inhibitory capacity; for example, TIMPs1 and 2 selectively inhibit MMP9 and 2, respectively (9). Increased expression of MMPs has been associated with poor prognosis and shortened patient survival in a variety of malignancies including carcinomas of the esophagus (10), stomach (11), colon (12), breast (13), pancreas (14), lung (15), kidney (16), and ovary (17). TIMP expression has been associated with both tumor suppressor or antimetastatic effects and tumor-promoting effects in selected cancers (18 -20

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

“…In addition, TIMP-2 has been shown to promote cell growth (Hayakawa et al, 1994). Enhanced amounts of TIMP-2 protein are found to be associated with prostate cancer malignancies (Ross et al, 2003), but for colon and gastric cancer the correlation with clinico-pathological parameters has not been established (Ring et al, 1997;Joo et al, 2000). In our study, the CT/TT variant of TIMP-2 303C4T was observed more frequently in undifferentiated gastric carcinomas (WHO classification) and it was associated with worse tumour-related survival of gastric cancer patients.…”

Cambodian Phellinus linteus Inhibits Experimental Metastasis of Melanoma Cells in Mice via Regulation of Urokinase Type Plasminogen Activator

“…26) However, unexpectedly, CPL did not exhibit the statistical significance, though CPL tended to inhibit the expression of MMP-2 and activate TIMP-2 by RT-PCR analysis.…”

No Association of Matrix Metalloproteinase [MMP]-2 (−735C > T) and Tissue Inhibitor of Metalloproteinase [TIMP]-2 (−418G > C) Gene Polymorphisms with Cervical Cancer Susceptibility

“…It is, therefore, reasonable to postulate that this polymorphism may downregulate TIMP-2 expression and consequently cause an imbalance between the activities of TIMP-2 and MMP-2, which is believed to have a significant impact on cancer development and progression [7,10].…”

“…Of the four members in the TIMP family, TIMP-2 is particularly interesting because of its dual functions in terms of regulating MMP-2 activity [5] and its paradoxical effects on certain cancers [6,7]. A single nucleotide polymorphism (-418G/C) has also been identified in the promoter of the TIMP2 gene [8].…”