Hypoxia-Mediated Decrease of Ovarian Cancer Cells Reaction to Treatment: Significance for Chemo- and Immunotherapies

Abstract

Hypoxia, a common factor ruling the microenvironment composition, leads to tumor progression. In this hypoxic context, cytokines and cells cooperate to favor cancer development and metastasis. Tumor hypoxia is heterogeneously distributed. Oxygen gradients depend on the vicinity, functionality of blood vessels, and oxygen ability to diffuse into surrounding tissues. Thus, the vasculature state modulates the microenvironment of the tumor cells. Cells sense and react to small variations in oxygen tension, which explains the lack of tumor cells’ unicity in their reaction to drugs. Ovarian cancers are highly hypoxia-dependent, ascites worsening the access to oxygen, in their reactions to both chemotherapy and new immunotherapy. Consequently, hypoxia affects the results of immunotherapy, and is thus, crucial for the design of treatments. Controlling key immunosuppressive factors and receptors, as well as immune checkpoint molecule expression on tumor, immune and stromal cells, hypoxia induces immunosuppression. Consequently, new approaches to alleviate hypoxia in the tumor microenvironment bring promises for ovarian cancer immunotherapeutic strategies. This review focuses on the effects of hypoxia in the microenvironment and its consequences on tumor treatments. This opens the way to innovative combined treatments to the advantage of immunotherapy outcome in ovarian cancers.

Progesterone Receptor Membrane Component (PGRMC)1 and PGRMC2 and Their Roles in Ovarian and Endometrial Cancer

“…As indicated, ovarian [ 86 ] and endometrial cancers [ 87 ] develop in a hypoxic environment in which vascular development is limited and the expression of genes that control numerous signal transduction and survival pathways are altered [ 88 ]. One example of changes that occur in both ovarian and endometrial cancers is an upregulation of efflux pumps that remove chemotherapeutic drugs from the cancer cells [ 84 ].…”

“…This process of self-renewal can be promoted by stem cell growth factor receptor, c-Kit, which is a tyrosine kinase oncoprotein that is expressed by ovarian [ 89 ] and endometrial [ 90 ] cancer stem cells. Moreover, c-Kit expression is induced by HIF1A [ 89 ], known to be highly expressed in cancers as they are in a hypoxic environment [ 86 , 88 ]. Although endometrial cancer stem cells have not been examined, ovarian cancer stem cells express PGRMC1 [ 91 ], which also stimulates stem cell self-renewal [ 82 ].…”

Differential expression of hypoxia-inducible factors related to the invasiveness of epithelial ovarian cancer

“…Therefore, alleviating hypoxia in ovarian cancer is essential for treatment efficacy. Targeting HIFs can help regulate angiogenesis, change the tumor microenvironment, increase the effect of chemotherapy, and help to overcome chemoresistance 5 .…”

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

“…This complex mixture of soluble factors accumulates due to leaky tumor vasculature as well as disrupted lymphatic patency ( 108 ). Given that ascites worsens tumor access to oxygen, ascites accumulation promotes the negative responses of the tumor to low oxygen ( 109 ). In addition, the flow of ascites fluid current dictates the direction of EOC secondary tumor dissemination within the abdominal cavity ( 108 ).…”