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.

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

“…4 CAFs are essential components of TME. They play pivotal roles in tumor progression in various types of tumor, such as lung cancer, 5 breast cancer, 6 pancreatic cancer. 7 CAFs are involved in many physiological processes such as epithelial-mesenchymal transition (EMT), chemoresistance, matrix remodeling, metastasis and immunosuppression by secreting cytokines and growth factors and creating an optimal microenvironment for tumor cells.…”

The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer

“…Other study showed that BRCA1 -deficient breast cancer cells can transform CAFs to their altered activated phenotype, which the authors named metastasis associated fibroblasts (MAFs). MAFs can subsequently induce metastatic changes in the breast cancer cells and accompany them during metastasis [ 69 ]. It was previously shown that BRCA1 colocalizes with Ezrin, Moesin, Radixin and F-actin and controls cell motility [ 70 ].…”

“…It was previously shown that BRCA1 colocalizes with Ezrin, Moesin, Radixin and F-actin and controls cell motility [ 70 ]. In connection with this information, MAFs induce changes in proliferation, invasion and migration of cancer cells, which are linked to the elevated expression of EMT markers, Ezrin and CCL5 in these cells [ 69 ].…”

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

“…Interestingly, inhibition of Ezrin and CCL5 in MAFs reduces their capability to promote cancer cell migration and invasion in vitro. Therefore, Ezrin and CCL5 could represent promising targets to prevent the differentiation of BCAFs into a more metastatic phenotype, especially in BRCA1 mutated tumors [ 206 ]. A recent study demonstrated that pBCAFs and metastatic BCAFs (mBCAFs) isolated from skin, lung, liver, and bone metastases exhibit distinct gene expression profiles.…”