Plasma Levels of Human Chitinase 3-like 1 (chi3l1), a Proangiogenic Protein, Are Persistently Elevated During the First Month After Minimally Invasive Colorectal Cancer Resection

H.m.c Shantha Kumara, PhD, Hiromichi Miyagaki, MDPhD, Xiaohong Yan, PhD, Sonali A C. Hearth, BS, Elizabeth Myers, MD, 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..

Blood levels of at least 6 proangiogenic proteins, including VEGF, monocyte chemotactic protein-1(MCP-1), and Interleukin-8(IL8), have been shown to be elevated for 2-4 weeks after minimally invasive colorectal resection (MICR). Chitinase 3-like 1 (CHI3L1) protein, also known as YKL-40, is a member of the Chitinase family of proteins and has chemotactic and proangiogenic effects similar to those of MCP-1 and IL8. This study’s goal was to assess blood levels of CHI3L1 for 2 months after MICR (lap. assisted or hand-assisted) for colorectal cancer (CRC). Tumor expression of CHI3L1 has been noted in patients with colon, breast, and hepatocellular carcinoma. CHI3L1 regulates cellular and tissue responses via IL-13 receptor alpha 2. CHI3L1 may utilize its chitin binding ability to communicate with other signal transduction pathways to modulate inflammation, apoptosis, tissue remodeling, cell growth and angiogenesis. CHI3L1 promotes in vitro cancer cell proliferation, macrophage recruitment, human endothelial cell migration and tube formation, and contributes to wound healing. The impact of MICR for CRC on plasma levels of CHI3L1 is unknown.

Patients enrolled in an IRB approved data/plasma bank who underwent elective MICR for CRC for whom adequate plasma samples were available were included. The prospectively gathered clinical, demographic, pathologic and short term outcome data were reviewed. Blood samples were collected preoperatively (PreOp) and at a variety of post operative (PostOp) time points. Plasma was isolated and stored at -80°C. Late samples were bundled into 7 day blocks and considered as single time points. CHI3L1 levels (ng/ml) were determined in duplicate via ELISA and results reported as mean± SD. The paired t-test was used for statistical analysis (significance p<0.008 after Bonferroni correction).

PreOp and, at least, 1 late postoperative plasma sample were available for 80 MICR cancer patients (colonic 60%; rectal 40%; 42 males /38 females, mean age 65.6± 12.8 years). The mean incision length was 7.8± 3.6 cm, mean operative time 308.3± 124.2min, and mean length of stay was 6.6± 4.3days. The final cancer staging breakdown was; Stage I, 25%, Stage II, 31.3%, stage III, 40% and stage IV, 3.7%. The mean PreOp CHI3L1 level was 93.3± 108.9ng/ml (n=80). When compared to PreOp levels significantly elevated (p<0.0001) mean CHI3L1plasma levels (mg/ml) were detected on POD1 (679.7± 405.2; n=79), POD 3 (204.7± 221.9, n=76), POD7-13 (182.9± 201.5, n=62), POD14-20 (225.3± 222.2, n=22, p=0.001), and POD 21-27 (145.0± 212.6., n=20, p=.002). No significant difference in plasma levels were noted on POD27-41 (vs. PreOp,n= 15,p=0.011).

Plasma CHI3L1 levels are significantly elevated over PreOp levels for a month after MICR for CRC. The increased blood levels during the early postoperative period may be associated with the short lived acute inflammatory response that occurs after surgery and resolves in the first week. In contrast, the later and persistent elevation noted during weeks 2-4 after MICR may be related to wound healing. Persistently elevated CHI3L1 levels, together with the similarly increased levels of the other proangiogenic proteins mentioned, may collectively promote the growth of residual tumor after MICR.

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