Targeting the Microenvironment in High Grade Serous Ovarian Cancer

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.

Keywords: angiogenesis; high-grade serous ovarian cancer; immune response; metastasis; therapeutic targeting strategies; tumor microenvironment.

Figure 1

The interplay between cancer and stromal cells in the tumor microenvironent TME regulates tumor growth and metastasis: as tumors grow, hypoxic stress and low nutrient availability drives the release of tumor-secreted growth factors and cytokines that exert paracrine effects on the surrounding stroma. Sustained exposure to tumor-derived transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) drives fibroblasts trans-differentiation into (cancer associated fibroblasts) CAFs. These factors also act upon endothelial cells, pericytes and immune cells to stimulate angiogenesis. CAF-derived 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. Adipocytes facilitate cells proliferation by providing energy dense lipids to the metastasized cancer cells. 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; conversely MDSC-secreted microRNA101 reprograms tumor cells to a stemness phenotype.

Figure 2

Ovarian cancer cells adhere to the mesothelial lining during tumor dissemination in the peritoneal cavity. Upon activation of EMT (epithelial-to-mesenchymal transition), cells progressively shed from the primary tumor into the peritoneal cavity (blue square). During the EMT process, there is a decrease in E-cadherin expression and increase in proteins associated to a mesenchymal phenotype, such as vimentin, tissue transglutaminase (TG2) and integrins. Cells that survive in the environment of the peritoneal cavity form spheroids. Spheroids attach to the fibronectin (FN) rich matrix secreted by the mesothelial cells, clear the subjacent monolayer and invade the underling tissue. These adhesion and invasion processes are mediated by interactions of integrin-β1 receptors with the FN fibrils in the ECM. Upon FN binding, α5β1 integrin receptors undergo clustering, which is enhanced by molecular bridges with TG2. Next, talin is recruited to the adhesion complex and provides the necessary traction force for the mesothelial monolayer displacement (red dotted bottom square). Also, “outside-in” signaling downstream of β1 integrin is activated, inducing focal adhesion kinase (FAK) phosphorylation. Therapeutic strategies targeting the TG2-FN-Iβ1 complex aim at interfering with the cell adhesion process and consequently preventing OC metastasis (red dotted top square).