MICR is associated with elevated plasma levels of MMP2 during the 1st month after surgery which may promote tumor growth & metastasis

Hmc Shantha Kumara, PhD1, Hiromichi Miyagaki, MDPhD2, Charles Petrick, BS1, Xiaohong Yan, MDPhD1, Linda Njoh, PhD1, Vesna Cekic, RN1, Nipa D Gandhi, MD1, Richard L Whelan, MD1. 1Department of Surgery, Mount Sinai Roosvelt Hospital, New York, USA, 2Department of Gastroenterological surgery,Osaka University,Osaka,Japan,

Introduction: Matrix Metalloproteinase -2(MMP-2) degrades type IV collagen, a major component of basement membranes. MMP-2 plays important roles in tissue remodeling and wound healing but has also been implicated in disease processes including cancer. Elevated MMP-2 activity has been linked to a poor prognosis in lung, breast, prostate and colorectal cancer (CRC). MMP-2, by degrading basement membrane, facilitates tumor cell invasion and metastasis formation.  MMP-2 is also thought to promote tumor angiogenesis by facilitating Endothelial Cell migration and VEGF release. The impact of minimally invasive colorectal resection (MICR) for CRC on plasma MMP-2 levels is unknown. This study’s aim was to measure plasma MMP-2 levels during the first postoperative (postop) month.

Method: CRC patients undergoing MICR who were enrolled in an IRB approved data/plasma bank for whom adequate plasma samples were available were eligible. Prospectively gathered clinical, operative and pathological data were utilized. Blood samples were collected Preop and at varying postop time points and were stored at -80C. Only patients for whom Preop, Postop day (POD) 1, 3 and at least 1 late postop plasma sample (POD 7-41) were available were included in the study. The late samples were bundled into 7 day time blocks and considered as single time points. MMP-2 levels were analyzed in duplicate via ELISA and the results reported as mean and ±SD .The paired t-test was used for analysis. (Significance,  p<0.008 after Bonferroni’s correction).

Results: A total of 101 CRC (rectal, 27%; colon, 63%) patients that underwent MICR were studied (51 males /49 female, mean age 66.5± 12.8 years). The mean incision length was 8.2 ± 4.2cm and mean LOS 6.8± 4.1 days. The cancer stage breakdown was: Stage I, 34%; Stage II, 29%; stage III, 33%; and stage IV, 5%.The mean PreOp MMP-2 level (ng/ml) was 176.8±40.6 (n=101). Significantly elevated mean plasma levels were noted on POD1 (213.0±49.2, n=100,p=< 0.0001), POD3 (256.3±65.9,n=90,p=< 0.0001), POD7-13(227.5±60.2,n=75,p=< 0.0001), POD 14-20 (236.0±45.9,n=29,p=0.003), POD 21-27 (231.0±64.2,n= 21,p=0.0003 and on POD 28-41 time point (261.7±61.1,n=18,p=0.0005).

Conclusion: Plasma MMP-2 levels are significantly elevated from baseline for over 4 weeks after CRC MICR. The etiology of these changes in unclear, however, surgical trauma-associated inflammation may account for the early increase whereas tissue remodeling associated with wound healing likely accounts for the mid and late postop elevations. Increased MMP-2 levels may promote tumor growth in residual tumor deposits and formation of metastases. Further study is warranted.

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