Hepatoselüler karsinomada kanser-bağlantılı fibroblastlar ile kanser hücrelerinin karşılıklı etkileşiminin analizi

Most anticancer treatment approaches focus on malignant cells. However, tumors do not only comprise of malignant cells, but also contain many other cell types such as fibroblasts, mesenchymal cells, epithelial cells and non-cellular components. Hence, the progression of a tumor also depends on its crosstalk with neighboring cells called tumor stroma. Stroma can be activated by various stimuli and affects tumor progression, metastasis and drug resistance. Among stromal cells, fibroblast have attracted a significant amount of attention in the last decade, due to their unique functions. Naive fibroblasts are quiescent, but they are activated during physiological events, such as wound healing. On cancer, in response to interactions with tumor cells, fibroblasts (and some other cell types) undergo transdifferentiation and turn into cancer-associated fibroblasts (CAFs). CAFs are distinguished from other types of activated fibroblasts. CAFs were shown to support tumor growth, invasion, metastasis and even cancer resistance to treatment. In this study we isolated primary fibroblasts of normal liver and CAFs from hepatocellular carcinoma (HCC) tissues, and analyzed their effects on cancer behaviour. Co-culture experiments showed that, HCC-derived CAFs, but not normal liver fibroblasts, supported the growth of HepG2 and Huh7 tumor cell lines. Moreover, tumor promoting effects of CAFs did not require direct cell contact, indicating involvement of secreted factors. We identified a factor playing a key role in the observed cancer cell-CAF crosstalk. Secretion level of the factor was higher in conditioned media from CAFs that were co-cultured with cancer cells compared to those co-cultured with tissue fibroblasts. We demonstrated that the factor was predominantly secreted from CAFs, and cancer cells showed much lower expression levels. Importantly, proliferative effects of CAFs on cancer cells was reversed when a factor-specific neutralizating antibody was added to co-cultures. Hence, we defined a key regulator of CAF-induced tumor growth in HCC. The identified factor might be a potential target for new anticancer therapy approaches.