Deciphering the stromal molecular interactions in the tumor microenvironment for developing novel therapeutic targets

Abstract

The tumor microenvironment (TME) has been found to be important for cancer growth and metastasis. Therefore, research is being actively conducted to characterize the major components of the TME that regulate tumor progression. Among the various types of cells that make up the TME, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) play a major role in affecting cancer progression by creating a pro- or anti-tumorigenic environment. Therefore, differentiation or activation through the interaction of these two cell types with each other is for a major focus of cancer research. Additionally, it has been shown that CAFs and TAMs have significant impacts on the outcome of chemotherapy and immunotherapy, supporting the importance of fully characterizing the interactions between CAFs and TAMs. Our previous research has shown that CAFs regulate differentiation into immunosuppressive, pro-tumorigenic M2 TAMs through GM-CSF and IL-6, regulatory molecules of CAFs by TAMs have not been clarified. So, this study seeks to identify molecules that can activate CAFs among cytokines secreted from TAMs. Among many markers to confirm activation of CAFs, α-SMA that is representative marker was first checked whether it was suitable, and then using it as a marker. Next, it was confirmed TGF-β, which is representative cytokines secreted from immunosuppressive M2 TAMs, activates normal fibroblasts into CAFs. When IL-6 and GM-CSF were treated, the expression of TGF-β in macrophages increased. Also, when these two cytokines were inhibited in a mouse colorectal cancer model using blocking antibodies, collagen deposition as well as the number of CAFs expressing α-SAM decreased. Furthermore, it was confirmed in vitro that the invasion of cancer cells is increased by these activated CAFs. Because CAFs in tumor microenvironment affect not only tumor progression but also drug resistance and metastasis that are limitation of existing chemotherapy, the finding in this research suggest a novel anticancer therapeutic targets.