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.

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…Recurrent OC remains a major challenge since there is >80% patient mortality within 5 years [6]. The failure of chemotherapy treatment in OC is a likely result of tumour heterogeneity, lack of targetable effects on tumour microenvironment, and the likely presence of pre-existing or acquired chemoresistant cancer cells or cancer stem cells (CSCs) [7,8].…”

CD3+CD56+ natural killer T cell infiltration is increased in cervical cancer and negatively correlated with tumour progression

“…Activity and killing effect of infiltrating NKT are inhibited in cervical cancer tissues, leading to increase of CD4 þ NKT cells that promote tumour progression and decrease of CD8 À CD4 À NKT cells that inhibit tumours Most tumour tissues have immunosuppressive microenvironment in which the activity of infiltrating immune cells is inhibited [39]. Tumour cells are a major component in the tissue microenvironment, and are involved in regulating the remodelling of the microenvironment [40].…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…Ovarian cancer metastasizes very early in the disease process. Malignant cells shed from the primary tumour, survive anchorage-independent apoptosis as free-floating cells or form spheroids, and spread throughout the peritoneal cavity to proliferate and interact with mesothelial cells and adipocytes of the omentum [ 71 , 72 ]. Ovarian cancer cells preferentially home to “milky spots” of the peritoneum [ 73 ], aggregates of immune cells, including macrophages, lymphocytes, and plasma cells supplied by blood and lymphatic vessels, which function as secondary lymphoid organs and promote immunity to peritoneal antigens [ 74 ].…”

“…In ovarian cancer, TAMs expressing B7-H4 (a member of the B7 superfamily; V-set domain containing T cell activation inhibitor 1, [ 83 ] gene) suppress the activation of antigen-specific T-cells; and CCL22 secreted by TAMs recruits CCR4-expressing Tregs and promotes tumour growth [ 84 ]. MDSCs are a mixed population of precursors of dendritic cells, macrophages and granulocytes at various stages of differentiation that are stimulated by tumour-derived factors, are potently immunosuppressive, and contribute to tumour progression [ 72 , 85 ]). They are found in some malignancies including ovarian, breast, colon, pancreatic and non-small cell lung cancer, and are associated with escape from host immunity and poor outcomes [ 86 , 87 ].…”

“…CAFs are phenotypically similar to activated fibroblasts found in wound healing tissue. They are derived predominantly from resident fibroblasts, however they can also arise by trans-differentiation of other cell types (e.g., epithelial, endothelial, pericytes, adipocytes, and bone marrow derived mesenchymal stem cells) in response to tumour derived factors [ 72 ]. These include TGFβ, PDGF-BB, bFGF, VEGF, microRNAs, reactive oxygen species (ROS), MMPs, and extracellular vesicles (EVs) [ 72 ].…”