Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment

Abstract

Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.

Keywords: cancer-associated fibroblasts; ovarian cancer; stromal-tumor crosstalk; tumor microenvironment.

Figure 1

Signaling crosstalk and its targeting in ovarian cancer. (A) Crosstalks between ovarian cancer cells and stromal CAFs promote tumor progression. Here, we illustrated three signaling crosstalk events between ovarian cancer cells and cancer-associated fibroblasts (CAFs). In the TGF-β-rich ovarian tumor microenvironment, Smad signaling was induced in CAFs through activation of TGF-β receptors. This stimulus increases the production of the CAF-derived secretory protein VCAN. VCAN, when acts on cancer cells, activates the NF-κB signaling, and subsequently promotes migration and invasion of cancer cells via the up-regulation of motility/invasion-related genes CD44, HMMR, and MMP9. On the other hand, CAF-derived MFAP5 binds to the α_Vβ₃ integrin on the cancer cell and activates the calcium-dependent FAK/CREB/TNNC1 signaling pathways, which subsequently stimulate the reorganization of the F-actin cytoskeleton, thereby enhancing ovarian cancer cell motility. CAF-derived chemokine (C-X-C motif) ligand 11 (CXCL11) promotes cancer cell growth and migration via activation of the chemokine (C-X-C motif) receptor type 3 (CXCR3) on the cancer cell surface; and (B) multiple approaches can be used to target specific components within the cancer cell/CAF crosstalk signaling networks. Gene silencing can down-regulate the tumor- or stroma-derived secretory ligands that promote tumor progression by delivering specific gene-targeting siRNAs into tumor cells or CAFs using nanoparticles. Secretory factors from cancer cells and CAFs can be targeted using blocking antibodies. In addition, if specific receptors are involved in the crosstalk signaling, small molecule inhibitors can be used to inhibit the activation of these receptors. Lastly, gene editing using CRISPR/Cas9 technology can be developed into a therapeutic approach to down-regulate tumor- or stroma-derived secretory ligands and signaling molecules.