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Introduction: YKL-40, a 40-kDa secreted glycoprotein also known as human cartilage-glycoprotein 39 or Chitinase 3-like 1, has recently been shown to promote cancer growth and progression through angiogenesis. Despite the correlation of high serum levels of YKL-40 with poor prognosis in colon cancer, the significance of tissue expression of YKL=40 is yet to be described. We have identified a unique pattern of expression using immunohistochemistry (IHC) on formalin-fixed paraffin-embedded material collected from 282 patients diagnosed with Stage II to IV colon cancer. Furthermore, our analysis identifies YKL-40 tissue expression to be highly predictive of prognosis in Stage II node-negative cancer. Methods and Materials: From our cohort, 216 patients were identified with Stage II disease. Employing a YKL-40 antibody, IHC was performed on archival tissue from primary tumors. Expression was measured by a scoring method based on intensity of staining and percentage of stained cells. Cox regression analysis correlated YKL-40 tissue expression with disease-free survival, controlling for stage and lymphatic invasion. Results: YKL-40 is uniquely expressed in both epithelial and stromal cells from colon cancers. With a median follow-up of 48 months, high expression of YKL-40 within the stroma of the tumor correlated with disease-free survival (p= 0.036) while controlling for other known prognostic variables. High expression within the tumor epithelium did not correlate with prognosis (p=0.241). Our results demonstrated that patients with high stromal expression of YKL-40 in their tumors were more than twice likely to relapse (hazard ratio 2.4 +/- 1.0).Conclusion: Our results confirm a pattern of expression of YKL-40 in colon cancer that may be a potential predictive biomarker to identify high risk patients with Stage II disease who warrant adjuvant therapy. Furthermore, the uniquely prognostic importance of YKL-40 expression within the stroma may be hypothesis-driven by emphasizing the role of the tumor stroma in cancer progression. The pro-angiogenic mechanism of YKL-40 could provide a more targeted approach towards the use of anti-angiogenic therapy for colon cancer. Our study warrants further validation and supports closer investigation into the tissue-specific mechanism of YKL-40.

High YKL-40 expression predicts worse disease-free survival. Level of expression (Low, Intermediate and High) defined by a scoring method incorporating intensity and percent of cells stained by IHC.