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.

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

“…In ovarian cancer, crosstalk between CAFs and cancer cells is associated with production of CAF-specific growth factors and ECM that can support tumor growth and metastasis (18).…”

Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance

“…Cancer-associated fibroblasts (CAFs), one of the primary stromal cell types in ovarian tumor tissues (6), secrete CAF-specific proteins, cytokines, and growth factors and produce an extracellular matrix (ECM) that supports tumor cell growth and angiogenesis and confers chemoresistance (7)(8)(9)(10)(11). However, the mechanisms by which CAFs promote angiogenesis in ovarian cancer remain poorly understood.…”

Berberine inhibits the chemotherapy‐induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer

“…However, in over 70% of ovarian cancer cases, patients usually recur within 12‐ to 24 months after initial diagnosis and die of progressively chemotherapy‐resistant disease . Considering the high rate of recurrence of ovarian cancer patients, new therapeutic strategies, especially against relapse after chemotherapy, are urgently needed …”

“…6 Considering the high rate of recurrence of ovarian cancer patients, new therapeutic strategies, especially against relapse after chemotherapy, are urgently needed. 7 Most common chemotherapeutics lead to the induction of apoptosis in the targeted cancer cell, including platinum-and taxane-based chemotherapy in ovarian cancer. 8 Although activation of the caspase 3 is a hallmark of apoptosis and usually tightly associated with response to chemotherapy, it also has been suggested a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells.…”