Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer

The aim of this study was to evaluate the cytomorphologic maturity and molecular activation of cancer-associated fibroblasts (CAFs) in the intratumoral stroma and invasive front in colorectal cancer and understand how they affect cancer invasion and long-term oncological outcomes. The cytomorphologic maturity of and alpha-Smooth muscle actin (alpha-SMA), fibroblast activation protein a (FAP alpha), and fibroblast-specific protein 1 (FSP-1) expression in CAFs in the intratumoral stroma (CAF(IT)) and the invasive front (CAF(IF)) of colorectal cancer tissues were compared (n=147). The correlations between CAF maturation, molecular activity markers, and cancer invasion were evaluated by network analysis. Overall survival and systemic recurrence were analyzed to assess the oncological effects of CAF properties. The cytomorphologic maturation rate was comparable between CAF(IT) and CAF(IF). The presence of mature CAFs was related to epidermal growth factor receptor overexpression in cancer cells. Expression rates of alpha-SMA (96.6%-98.0%) and FAP alpha (18.6%-22.9%) were similar between CAF(IT) and CAF(IF). FSP-1 expression was more frequent in CAF(IT) than in CAF(IF) (66.4% vs 58.2%, P=.038). There was a significant decrease in FSP-1 expression in CAF(IT) and CAF(IF) in higher stages. The infiltrating growth pattern of the tumor was more frequent in the immature CAF(IT). In colorectal cancer with perineural invasion and lymph node metastasis, FSP-1 expression in CAF(IF) was significantly lower. On multivariate analysis using the Cox proportional hazards model, immature CAF(IF) was found to be an independent prognostic factor of overall survival. In non-metastatic (stage I-III) colorectal cancer patients, CAF maturity was not a prognostic factor for systemic recurrence. Cytomorphologic maturity and molecular activation markers were similar between CAFs in the intratumoral stroma and invasive front of colorectal cancer.