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Colorectal Cancer Is Associated With Elevated Plasma Levels of MMP2
H M C Shantha Kumara*1, Hiromichi Miyagaki1,2, Xiaohong Yan1, Vesna Cekic1, Linda Njoh1, Nipa D. Gandhi1, Richard L. Whelan1
1Department of Surgery,Division of Colon and Rectal surgery, Mount Sinai Roosevelt Hospital, New York, NY; 2Department of Surgery, Saiseikai Senri Hospital 1-1-6, Tsukumodai,, Suita, Osaka, Japan
Introduction: Matrix Metalloproteinase 2 (MMP 2) also known as Gelatinase A, is one of the zinc-dependent extracellular matrix remodeling enzymes. MMP 2 which breaks down the extracellular matrix (ECM) participates in numerous pathological processes including inflammation and cancer growth. In the setting of cancer, up-regulation of MMP-2 aggravates the loss of basement membrane type IV collagen and the destruction of the ECM which promotes tumor progression and local invasion. MMP-2 also plays a role in tumor angiogenesis and, in particular, promotes the growth of tumors with angiogenic and metastatic phenotypes. Elevated levels of MMP2 have been found in breast, brain, ovarian, pancreas, colorectal, bladder, prostate and lung cancers. This study’s purpose was to compare preoperative (PreOp) plasma MMP2 levels in colorectal cancer (CRC) and benign colon disease patients (pts).
Method: Pts undergoing colorectal resection for CRC or benign colonic pathology (BCP) that had been prospectively enrolled in an IRB approved tissue and data bank for whom adequate PreOp plasma samples were available were studied. Demographic, clinical, operative and pathologic data were collected. MMP2 levels in preop plasma samples were determined via ELISA in duplicate and reported as median 95%CI. The Wilcoxon/Kruskal-Wallis test was used compare the results of two groups (significance p<0.05). The expressions levels of MMP2 in self-paired CRC and normal colonic mucosal specimens were assessed by RT-PCR. Receiver Operating characteristic (ROC) curve and area under the ROC curve (AUC) analysis assessed the feasibility of using plasma MMP2 as a diagnostic tool for CRC.
Results: A total of 168 CRC (73% colon, 27% rectal) and 128 BCP pts (diverticulitis 50%, adenoma 32%, other 18%) were studied. The CRC Stage breakdown was: Stage 1,29%; Stage 2, 27%, Stage 3, 32%, Stage 4, 12%. The median plasma MMP2 levels were significantly higher in the CRC group than in the BCP group(194.9,CI: 165.6,188.6 vs.159.8,CI: 170.4, 189.6;P=< 0.001 ). The AUC for the ROC curve (AUC) for plasma MMP2 in association with a diagnosis of CRC was 0.696 (sensitivity 55%, specificity 80%). 38 % of the CRC tumors tested (6/16) showed elevated MMP-2 expression vs. paired normal tissue.
Conclusion: The median MMP2 level was 22% higher in CRC pts. ROC curve evaluation suggests that plasma MMP2 analysis holds promise as a CRC diagnostic tool. The added MMP2 may be generated by the cancer cells themselves or the tumor associated stromal and/or inflammatory cells; alternatively, it may be related to tumor angiogenesis. Further study of larger groups of healthy control CRC pts is warranted.
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