In addition to benign fibrotic processes, CCN2 overexpression is also known to be responsible for pathologic fibrosis, including desmoplastic reaction in cancer. Inhibition of TGF-b, which is typically activated in HCCs with fibrous stroma, was reported to downregulate CCN2 and block tumor-stroma crosstalk and tumor progression in HCC. Two prior studies assessing the prognostic effects of CCN2 expression in HCCs disclosed that the expression levels of intra tumoral CCN2 were significantly higher in HCCs with bone metastasis. Moreover, the CCN2 mRNA was expressed in tumor cells of EMT-phenotype in HCC, facilitating migration, invasion, and progression of the tumor cells in vitro. In accordance with these studies, we discovered that CCN2 expression is related to more infiltrative growth without tumor capsule and worse DFS in HCCs. Although CCN2 is well known as fibrogenic cytokine, to our knowledge, no study has reported on a relationship between CCN2 expression and tumor fibrous stromal components in HCC. Herein, we demonstrated significant CCN2 expression in HCCs with fibrous stroma and even greater expression in scirrhous HCCs. The expression of CCN2 was correlated with absence of capsule formation, which is a characteristic pathological feature of invasive tumor growth, as well as frequent K19 expression, larger tumor size, and shorter disease free survival. Furthermore, expression of CCN2 was shown to be associated with EMA expression in both cohorts, which seems to be important in epithelial-stromal interactions in HCC. Taken together, we suggest that CCN2 expression is involved in the activation of CAFs and tumor fibrous stroma formation, which is related to the aggressive biological behavior of HCC. Interestingly, CCN2 expression was well correlated with K19 expression in the HCC specimens of this study. We previously reported that HCCs expressing stemness-related markers, such as K19, exhibited greater formation of fibrous stroma, more vascular invasion, and more aggressive clinical outcomes upon activation of EMT-related genes. The correlations between CCN2, K19, and fibrous stroma are of interest, in that they might imply that stemness is regulated by tumor stroma, as in various other tumors. Accordingly, the underlying molecular mechanisms thereof should be further investigated, as delineating the micro environmental regulation of stemness might provide new targets for cancer therapy. In conclusion, the expressions of CCN2, EMA, and FAP may be involved in the formation of tumor fibrous stroma, along with activation of CAFs in HCC, Staurosporine giving rise to aggressive behavior. Significant correlation between EMA-expressing tumor cells and FAP-expressing CAFs and their topographic closeness suggest possible cross-talk between epithelial cells and stromal cells in the tumor microenvironment of HCC. Genomic information has been proposed to be utilized as the basis for “personalized” health care. Interindividual variation in a drug response among patients has been well documented to cause serious problems in pharmacotherapy. This variation may be due to multiple factors such as disease phenotypes, genetic and clinical parameters.