Minimally Invasive Colorectal Resection Is Associated with Significantly Elevated Levels of Plasma Matrix Metalloproteinase 3 (mmp3) During the First Month After Surgery Which May Promote the Growth of Residual Metastases

H.m.c Shantha Kumara, PhD, Xiaohong Yan, PhD, Hiromichi Miyagaki, MDPhD, Sahani De Silva, Vesna Cekic, RN, Richard L Whelan, MD. Division of Colon and Rectal Surgery, Department of Surgery, St Luke’s-Roosevelt Hospital Center, Suite 7B, 425 West, 59th Street, New York, NY 10019, USA;Department of Gastroenterological surgery, Graduate school of Medicine, Osaka University..

MMP3, a member of the matrix metalloproteinase (MMP) family, is involved in the breakdown of extracellular matrix in normal physiologic processes such as tissue remodeling and may also play a role in cancer progression and metastasis.
Minimally invasive colorectal resection (MICR) may increase plasma MMP3 levels directly via surgical trauma or indirectly due to surgery associated elevations in TNF- α, and IL1 which are biosynthetic regulators of MMP3. Over expression of MMP3 has been demonstrated in patients with breast, lung and colorectal cancer (CRC). MMP3 activates other MMPs such as MMP7 and MMP9 and is crucial in connective tissue remodeling. Together with its activator mtariptase, MMP3 has also been associated with the promotion of angiogenesis and wound epithelialization. The impact of MICR for CRC on plasma levels of MMP3 is unknown. This study’s purpose was to evaluate plasma MMP3 levels during first month after MICR for CRC.

Patients enrolled in an IRB approved data/plasma bank who underwent elective MICR for CRC for whom adequate plasma samples were available were included in this study. Clinical, demographic and pathological data were prospectively gathered. Blood samples had been collected PreOp and at varying postoperative (Postop) time points and were stored at -80C. Only patients for whom PreOp, Postop day (POD) 1, 3 and at least 1late postop plasma sample (POD7-34) were available were included in this study. The late samples were bundled into 4 time periods (POD7-13, POD14-20, POD21-27, and POD 28-34) and considered as single time points. MMP3 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).

A total of 73 CRC patients who underwent MICR met the inclusion criteria (34 males /39 female, mean ages 66.3± 12.8 years; 28% rectal and 62% colon lesions). The mean incision length was 7.8 ± 3.6cm and mean length of stay was 6.8± 4.4 days. The final cancer staging breakdown was; Stage I, 27%, Stage II, 33%, stage III, 36% and stage IV, 4%. The mean PreOp MMP3 level was 14.9±7.8 ng/ml (n=73). Significantly elevated mean plasma levels were noted on POD1 (21.4±14.7ng/ml, n= 73, p=< 0.0001), POD3 (37.9±21.5 ng/ml, n= 72, p=< 0.0001), POD7-13 (22.0±13.0 ng/ml, n=56, p=< 0.0001), POD14-20 (21.9±10.3 ng/ml, n=20, p=0.003) and on POD 21-27 (21.9±11.43 ng/ml, n= 20, p=0.002) when compared to PreOp levels. Plasma levels returned to the PreOp baseline at the POD 28-41 time point (n=16, p=0.07).

Plasma MMP3 levels remained significantly elevated from baseline for 4 weeks after MICR for CRC. The cause of the MMP3 elevations in the early postop period may be the short lived surgery-related acute inflammatory response which includes elevations in blood IL-1 and TNF levels. The increases during weeks 2-4 may be related to wound healing. Increased MMP-3 levels may promote metastases or the growth of residual cancer. Larger studies are warranted to validate these findings and to determine the clinical effects, if any, of elevated MMP-3 levels.

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