Recent advances in understanding the metabolic plasticity of ovarian cancer: A systematic review

Abstract

Epithelial ovarian cancer (EOC) is a gynecologic malignancy with a poor prognosis due to resistance to first-line chemotherapeutic agents. Some cancer cells are primarily dependent on glycolysis, but others favor mitochondrial oxidative phosphorylation (OXPHOS) over glycolysis. Changes in metabolic reprogramming have been reported to be involved in cancer cell survival. In this review, we summarize the metabolic profiles (e.g., metabolic heterogeneity, plasticity, and reprogramming) and adaptation to the dynamic tumor microenvironment and discuss potential novel therapeutic strategies. A literature search was performed between January 2000 and March 2022 in the PubMed and Google Scholar databases using a combination of specific terms. Ovarian cancer cells, including cancer stem cells, depend on glycolysis, OXPHOS, or both for survival. Several environmental stresses, such as nutrient starvation or glucose deprivation, hypoxic stress, acidification, and excessive reactive oxygen species (ROS) generation, reprogram the metabolic pathways to adapt. The interaction between tumors and adjacent stromal cells allows cancer cells to enhance mitochondrial energy metabolism. The metabolic reprogramming varies depending on genomic and epigenetic alterations of metabolism-related genes and the metabolic environment. Developing accurate and non-invasive methods for early identification of metabolic alterations could facilitate optimal cancer diagnosis and treatment. Cancer metabolism research has entered an exciting era where novel strategies targeting metabolic profiling will become more innovative.

Keywords: Glycolysis; Metabolic plasticity; Metabolic reprogramming; Ovarian cancer; Oxidative phosphorylation; Stem cells; Warburg effect.

Figure 1

The number of articles identified by searching for keyword combinations. Figure shows the number of articles identified by keyword combinations and the number of records identified through database searching, records after duplicate removal, records screened, removal of inappropriate articles by reading full-text articles, and full-text articles assessed for eligibility.

Figure 2

The key regulators of metabolic profiles in ovarian cancer. A schematic diagram of the glycolysis pathway with metabolites (square boxes) [60]. The chief regulatory molecules that either promote (yellow box and red letters) or suppress (purple box and white letters) glycolytic enzymes are shown [60]. The blue and orange arrows indicate the metabolic shift toward glycolysis and OXPHOS, respectively.

Figure 3

Metabolic profile of ovarian cancer in the tumor microenvironment. The upper row (A and B) shows ovarian CSCs, and the lower row (E, D, and E) shows non-CSCs. A, C, and E cells favor glycolysis over OXPHOS, and B and D cells predominantly prefer OXPHOS. Dotted arrows indicate adaptive metabolic plasticity.