Abstract
Cancer–stroma interactions play a key role in cancer progression and response to standard chemotherapy. Here, we provide a summary of the mechanisms by which the major cellular components of the ovarian cancer (OC) tumor microenvironment (TME) including cancer-associated fibroblasts (CAFs), myeloid, immune, endothelial, and mesothelial cells potentiate cancer progression. High-grade serous ovarian cancer (HGSOC) is characterized by a pro-inflammatory and angiogenic signature. This profile is correlated with clinical outcomes and can be a target for therapy. Accumulation of malignant ascites in the peritoneal cavity allows for secreted factors to fuel paracrine and autocrine circuits that augment cancer cell proliferation and invasiveness. Adhesion of cancer cells to the mesothelial matrix promotes peritoneal tumor dissemination and represents another attractive target to prevent metastasis. The immunosuppressed tumor milieu of HGSOC is permissive for tumor growth and can be modulated therapeutically. Results of emerging preclinical and clinical trials testing TME-modulating therapeutics for the treatment of OC are highlighted.
Highlights
High-grade serous ovarian cancer (HGSOC) comprises the majority of epithelial ovarian tumors, is associated with a p53-mutated signature and is characterized by initial sensitivity to platinum and a unique pattern of dissemination in the peritoneal space
The β1 integrin–FN interaction is further enhanced by the bridging activity of TG2, a protein we discovered to be overexpressed in OC [122]
Anti-angiogenic therapy in combination with chemotherapy has significantly improved the survival of women with advanced OC and has become part of the standard approach
Summary
High-grade serous ovarian cancer (HGSOC) comprises the majority of epithelial ovarian tumors, is associated with a p53-mutated signature and is characterized by initial sensitivity to platinum and a unique pattern of dissemination in the peritoneal space. The sub-peritoneal stroma contains a collagen-based matrix, activated fibroblasts, blood vessels, and lymphatics This unique milieu permits accumulation of factors secreted by both cancer and stromal cells and enables metastatic seeding and tumor proliferation. Chemokines, cytokines, and growth factors commonly secreted in the tumor microenvironment (TME) include the stromal cell-derived factor (SDF1), interleukin-6. As the rich TME protects cancer cells from noxious stimuli promoting tumor growth (Figure 1), its disruption through targeted therapy could arrest cancer progression. FGF and hepatocyte growth factor (HGF) promote tumor cell proliferation, CAF-derived matrix metalloproteinases (MMPs) promote invasion while chemokine ligand 14 (CXCL14) and transforming growth factor-α (TGF-α) enhance metastasis. Ovarian cancer (OC) cell-derived TGF-β1 upregulates fibronectin secretion in mesothelial cells, which in turn enhances spheroid adhesion to the peritoneal wall. Cancer cells expressing Snail and chemokine (C-X-C motif) ligand 1/2 (CXCL1/2) recruit myeloid-derived suppressor cells (MDSCs) to the tumor site; MDSC-secreted microRNA101 reprograms tumor cells to a stemness phenotype
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