Thus, we attempted to evaluate the expressions of CCN2, EMA, and FAP and their correlation with clinicopathological features of HCCs. As well, their topographic expression patterns were further examined in HCCs with abundant fibrous stroma. Tumor behavior is affected by not only malignant tumor cells themselves but also by the tumor microenvironment, including CAFs. Although, HCCs usually show no or only little amounts of fibrous stroma, in our previous study, we found that so called scirrhous HCCs, HCCs with abundant fibrous stroma, exhibit an aggressive biological behavior, along with expression of stemness-related markers and activation of TGF-b signature and EMT-related genes. These findings suggest tumor-stroma interaction in HCC; however, the activation mechanisms thereof remain unclear. FAP was initially identified as being expressed in reactive fibroblasts for embryonic development or in chronic inflammation. More importantly, FAP is recognized as a marker of CAFs, and is reported to increase stromal cell proliferation and invasiveness, reduce cell apoptosis, and to be associated with worse prognosis in colon cancer and pancreas cancer. The present study found that FAP is expressed predominantly in CAFs from the tumor fibrous stroma of HCCs, and is significantly correlated with frequent vascular invasion in scirrhous HCCs. In contrast, FAP expression was rarely found in benign fibrotic tissue of chronic hepatitis/cirrhosis. These findings suggest that FAP is involved in the activation of CAFs in tumor stroma, which differ from benign fibroblasts in the fibrous tissue of chronic hepatitis/cirrhosis. An in vitro co-culture model study of human hepatoma cells and activated HSCs demonstrated increases in EMA mRNA when those cells were cultured together, compared to culture of stromal cells alone. Our study revealed significantly higher rates of EMA expression in HCCs with fibrous stroma, compared to those without, and this was related to poor DFS in scirrhous HCC patients. These findings were consistent with previous reports that EMA was a poor prognostic factor in HCC. Interestingly, in HCCs with large tumor nests, EMA expression was higher at the peripheral portions of the tumor nests where tumor cells were more closely in contact with FAP-expressing CAFs. Meanwhile, in HCCs with small nest/trabecular pattern, EMA expression was rather diffuse: the tumor cells closely intermingled with CAFs expressing FAP. This topographic expression pattern that suggests topographic closeness between the EMA-expressing tumor cells and CAFs of tumor stroma, which was similar to that of K19 expression in HCCs with fibrous stroma reported in our previous study. Furthermore, the frequency of EMA expression was shown to be significantly correlated with that of FAP expression in scirrhous HCCs. Taken together, we Fulvestrant clinical trial discerned that EMA and FAP may be important in tumor-stroma cross-talk via activation of CAFs. To our knowledge, this is the first study to verify topographically the expression patterns of EMA in human HCC tissues with activated CAFs. CCN2 is a fibrogenic cytokine that mediates almost all fibrotic processes. Overexpression of CCN2 in fibroblasts produces large amounts of extracellular matrix and enhances.