Brcal Defective Breast Cancer Cells Induce in vitro Transformation of Cancer Associated Fibroblasts (CAFs) to Metastasis Associated Fibroblasts (MAF)

Abstract

It is known that Cancer Associated Fibroblast (CAFs) from the primary tumor site can accompany cancer cells to a secondary site during the process of metastasis. We hypothesize that these CAFs could be transformed to an altered cell type, which can be called as Metastasis Associated Fibroblasts (MAF) in turn can support, and convoy cancer cells for metastasis. There are no published reports that have characterized and distinguished CAFs from MAF. It is well established that some of the cancer cells within the tumor mass accumulate novel mutations prior to metastasis. Hence, we speculated that mutations in the tumor suppressor gene, BRCA1, which is already reported to induce metastasis via abnormal expression of Ezrin, Radixin and Moesin (ERM), could generate MAF. In the present study, we demonstrate for the first time that CAFs isolated from primary breast cancer tissues when co-cultured with BRCA1 mutated HCC1937 cells transform CAFs to MAF in vitro. As expected, MAF augmented proliferation, migration and invasion along with over-expression of epithelial mesenchymal transition (EMT) markers, Ezrin and CCL5, thereby facilitating metastasis. Therefore, we inhibited Ezrin and CCL5 in vitro in MAF and observed that the migration and invasion abilities of these cells were attenuated. This highlights the intriguing possibilities of combination therapy using MAF inhibitors as anti-metastatic agents along with anticancer drugs, to control the metastatic spread from primary tumor site.