Surgery and aggressive chemotherapy has a 20% success rate in ovarian cancer (OvCa) meaning new therapies are desperately needed. Ovarian tumors are composed of 7-83% stroma, which drives tumor progression, increases angiogenesis, and promotes metastasis, yet current therapies are aimed at targeting the cancer cells alone 1,2. While the tumor stroma consists of a number of cell types, cancer associated fibroblasts (CAFs) are a major constituent. The Lengyel and Peter labs recently reported that in ovarian CAFs, the micro-RNAs (miRNA) miR-31 and miR-214 are downregulated while miR-155 is upregulated when compared to normal or tumor-adjacent fibroblasts 3. Additionally, it was shown that OvCa cells are sufficient to reprogram normal omental fibroblasts (NOFs) into CAFs through downregulation of miR-214, miR-31, and upregulation of miR-155 during coculture. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs as defined by increased fibroblast motility and promotion of tumor progression both in vitro and in vivo. Furthermore, the reverse experiment resulted in the reversion of CAFs into normal fibroblasts3. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function 3. The most highly upregulated chemokine, CCL5, was found to be a direct target of miR- 214 3. These results indicate that during the process of ovarian cancer progression, NOFs are reprogrammed to become CAFs through the regulation of miRNA expression. However, the factors and the mechanisms in which OvCa regulates NOF to CAF reprogramming through these miRNAs are not understood. Therefore I propose to determine the cancer-derived factors and the fibroblast signaling pathways that regulate the expression of miR-155, miR-214, and miR-31 during NOF to CAF reprogramming, which would result in the identification of key factors and mechanisms used by ovarian cancer to reprogram the tumor stroma.
Ovarian tumors are composed of 7-83% stroma, which drives tumor progression, increases angiogenesis, and promotes metastasis. However, current therapies used to treat OvCa focus on the genetic mutations of cancer cells or non-specifically target OvCa cells based on their increased proliferative rate. Thus, the benefits of identifying th mechanisms and factors involved in OvCa driven reprogramming of NOFs will elucidate novel drug targets that can be used individually to target the stroma or in combination to enhance the efficacy of current treatments that focus specifically on the cancer cells.
|Kohlhapp, F J; Mitra, A K; Lengyel, E et al. (2015) MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment. Oncogene 34:5857-68|