Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2021; 13(8): 879-892
Published online Aug 15, 2021. doi: 10.4251/wjgo.v13.i8.879
Plasma MMP-2 and MMP-7 levels are elevated first month after surgery and may promote growth of residual metastases
HMC Shantha Kumara, Hiromichi Miyagaki, Sajith A Herath, Erica Pettke, Xiaohong Yan, Vesna Cekic, Richard L Whelan
HMC Shantha Kumara, Xiaohong Yan, Vesna Cekic, Richard L Whelan, Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
Hiromichi Miyagaki, Department of Gastroenterological Surgery, Osaka University, Suita 565-0862, Osaka, Japan
Sajith A Herath, Analytic Department, Novartis, Morris Plains, NJ 07905, United States
Erica Pettke, Department of Surgery, Swedish Medical Center, Seattle, WA 98122, United States
Richard L Whelan, Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, United States
Author contributions: Shantha Kumara H contributed to the conception, design, sample processing, statistical analysis and interpretation of data, and revision of the articles; Miyagaki H, Herath SA and Yan X contributed to collection of human material clinical data, revision of the article; Pettke E and Cekic V contributed to human sample collection, processing, analysis and interpretation of data; Whelan RL contributed to the conception, design, interpretation of data, critical revision of the article; all authors drafted the article and made critical revisions and approved the submitted final version of the article to be published.
Supported by Thompson Family Foundation to the Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York.
Institutional review board statement: This study was reviewed and approved by Institutional Review Board of the Columbia university medical center, New York and Institutional Review Board of the Mount Sinai Hospital, New York.
Conflict-of-interest statement: All authors have no conflicts of interest or financial ties to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Richard L Whelan, FACS, MD, Professor, System Chief, Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, Third Avenue, Suite PH, New York, NY 10028, United States. rwhelan1@northwell.edu
Received: January 20, 2021
Peer-review started: January 20, 2021
First decision: February 14, 2021
Revised: March 16, 2021
Accepted: June 4, 2021
Article in press: June 4, 2021
Published online: August 15, 2021
Processing time: 205 Days and 11.4 Hours
Abstract
BACKGROUND

MMP-2 also known as gelatinase A and MMP-7 (matrilysin) are members of the zinc-dependent family of MMPs (Matrix metalloproteinase). MMP-2 and MMP-7 are remodeling enzymes that digest extracellular matrix; MMP-2 is extensively expressed during development and is upregulated at sites of tissue damage, inflammation, and in stromal cells of metastatic tumors. MMP-7 is expressed in the epithelial cells and in a variety of cancers including colon tumors. Plasma MMP-2 and MMP-7 levels were assessed before and after minimally invasive colorectal resection for cancer pathology.

AIM

To determine plasma MMP-2 and MMP-7 levels before and after minimally invasive colorectal resection for cancer pathology.

METHODS

Patients enrolled in a plasma bank for whom plasma was available were eligible. Plasma obtained from preoperative (Preop) and postoperative blood samples was used. Only colorectal cancer (CRC) patients who underwent elective minimally invasive cancer resection with preop, post-operative day (POD) 1, 3 and at least 1 late postop sample (POD 7-34) were included. Late samples were bundled into 7 d blocks (POD 7-13, 14-20, etc.) and treated as single time points. Plasma MMP-2 and MMP-7 levels were determined via enzyme-linked immunosorbent assay in duplicate.

RESULTS

Total 88 minimally invasive CRC resection CRC patients were studied (right colectomy, 37%; sigmoid, 24%; and LAR/AR 18%). Cancer stages were: 1, 31%; 2, 30%; 3, 34%; and 4, 5%. Mean Preop MMP-2 plasma level (ng/mL) was 179.3 ± 40.9 (n = 88). Elevated mean levels were noted on POD1 (214.3 ± 51.2, n = 87, P < 0.001), POD3 (258.0 ± 63.9, n = 80, P < 0.001), POD7-13 (229.9 ± 62.3, n = 65, P < 0.001), POD 14-20 (234.9 ± 47.5, n = 25, P < 0.001), POD 21-27 (237.0 ± 63.5, n = 17, P < 0.001,) and POD 28-34 (255.4 ± 59.7, n = 15, P < 0.001). Mean Preop MMP-7 level was 3.9 ± 1.9 (n = 88). No significant differences were noted on POD 1 or 3, however, significantly elevated levels were noted on POD 7-13 (5.7 ± 2.5, n = 65, P < 0.001), POD 14-20 (5.9 ± 2.5, n = 25, P < 0.001), POD 21-27 (6.1 ± 3.6, n = 17, P = 0.002) and on POD 28-34 (6.8 ± 3.3, n = 15 P < 0.001,) vs preop levels.

CONCLUSION

MMP-2 levels are elevated for 5 wk and MMP-7 levels elevated for weeks 2-6. The etiology of these changes in unclear, trauma and wound healing likely play a role. These changes may promote residual tumor growth and metastasis.

Keywords: Effects of surgery; Colorectal resection; Colorectal cancer; Plasma MMP-2 and MMP-7 levels; Angiogenesis

Core Tip: Our past studies have shown that the levels of 9 plasma proteins that play a role in angiogenesis have been shown to be elevated, vs baseline levels, for 2-5 wk after minimally invasive colorectal cancer resection (MICR). This group of proteins includes vascular endothelial-derived growth factor, placental growth factor, angiopoietin-2, soluble vascular adhesion molecule-1, monocyte chemo-attractant protein-1, chitinase 3-like-1, interleukin-8, CXCL16 and MMP-3 (matrix metalloproteinase-3). We have demonstrated that postoperative plasma from colorectal cancer (CRC) patients stimulates in vitro endothelial cell proliferation, migration, and invasion. This manuscript is to demonstrate that proangiogenic proteins, plasma MMP-2 and MMP-7 in CRC patients remain elevated for month after MICR.