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

Abstract

Epithelial ovarian cancer is predominantly diagnosed at advanced stages which creates significant therapeutic challenges. As a result, the 5-year survival rate is low. Within ovarian cancer, significant tumor heterogeneity exists, and the tumor microenvironment is diverse. Tumor heterogeneity leads to diversity in therapy response within the tumor, which can lead to resistance or recurrence. Advancements in therapy development and tumor profiling have initiated a shift from a “one-size-fits-all” approach towards precision patient-based therapies. Here, we review aspects of ovarian tumor heterogeneity that facilitate tumorigenesis and contribute to treatment failure. These tumor characteristics should be considered when designing novel therapies or characterizing mechanisms of treatment resistance. Individual patients vary considerably in terms of age, fertility and contraceptive use which innately affects the endocrine milieu in the ovary. Similarly, individual tumors differ significantly in their immune profile, which can impact the efficacy of immunotherapies. Tumor size, presence of malignant ascites and vascular density further alters the tumor microenvironment, creating areas of significant hypoxia that is notorious for increasing tumorigenesis, resistance to standard of care therapies and promoting stemness and metastases. We further expand on strategies aimed at improving oxygenation status in tumors to dampen downstream effects of hypoxia and set the stage for better response to therapy.

Energy Substrate Transporters in High-Grade Ovarian Cancer: Gene Expression and Clinical Implications

“…Furthermore, recent studies demonstrated that MCT4 expression is triggered by hypoxia and mediated by HIF-1α, while MCT1 expression is not enhanced in this case [ 45 ]. Highly hypoxic areas are usually increased in large tumor lesions, along with inadequate blood flow and ascites in the tumor milieu [ 6 ]. Therefore, HIF-1α can be a plausible factor contributing to resistance to carboplatin via alterations in cancer cell metabolism by enhanced MCT4 expression [ 46 ].…”

“…High-grade serous carcinoma (HGSC) is the most common subtype, accounting for over 70% of epithelial ovarian cancers (EOCs). The hallmark feature of HGSC is the diversity in the morphology of different cancer cells, depending on their intratumoral spatial localizations and the tumor microenvironment [ 6 ], leading to widely diverse drug resistance mechanisms [ 7 ].…”

Cancer Stem Cells in Ovarian Cancer—A Source of Tumor Success and a Challenging Target for Novel Therapies

“…OCSC niches are very specific because of the inflammatory and immunosuppressive milieu of the peritoneal cavity, where OC implants show exceptional tropism towards fatty tissue (omentum, colon appendices) and highly vascularized peritoneal immune collections called milky spots, which are followed by the production and accumulation of ascites [ 397 , 398 ]. Ascites is rich in immunosuppressive cytokines and contains increased numbers of immune tolerant PD-1 and CTLA-4 expressing T cells [ 399 , 400 ]. This unique environment also plays an important role in the creation of specific TIME where several immune cell types, including TAMs, TANs, DCs, Tregs, and MDSCs cells support tumor progression, chemoresistance, and immune evasion [ 401 ].…”

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

“…Pyruvate dehydrogenase kinase 1 activity inhibits pyruvate dehydrogenase, contributing to a shortage of pyruvate availability for the tricarboxylic acid cycle [ 17 ]. In turn, this lack of pyruvate decreases mitochondrial oxygen consumption and increases intracellular oxygen availability, to ultimately promote tumor cell survival [ 18 , 19 ]. Additionally, tumor cells have altered mitochondrial gene expression, including increased ubiquinol-cytochrome C reductase complex assembly factor 3 expression, which contributes to increased hypoxia by promoting a positive feedback loop with mitochondrial reactive oxygen species (ROS) to stabilize HIF-1α expression and enhance glycolysis [ 20 ].…”

“…As tumor heterogeneity causes significant disparities in therapeutic responses within the tumor, often leading to recurrence or resistance [ 19 ], it is critical to understand these unique components of the tumor from a therapeutic perspective to optimize therapy efficacy. To take advantage of the addition of a statin to boost cancer therapeutic strategies, we must optimize and better understand the myriad of variables influencing statin drug efficacy.…”