title: Metabolic orchestration between cancer cells and tumor microenvironment as a co-evolutionary source of chemoresistance in ovarian cancer: a therapeutic implication.
abstract: Our group reported a significant association between hexokinase II overexpression and chemoresistance in ovarian cancer, suggesting that aerobic glycolysis in the so-called Warburg effect might contribute to cancer progression. However, a growing body of evidence indicates contradictory findings with regard to the Warburg effect, such as high mitochondrial activity in highly invasive tumors and low ATP contribution of glycolysis in ovarian cancer. As a solution for the dilemma of the Warburg effect, the "reverse Warburg effect" was proposed in which aerobic glycolysis might occur in the stromal compartment of the tumor rather than in the cancer cells, indicating that the glycolytic tumor stroma feed the cancer cells through a type of symbiotic relationship. The reverse Warburg effect acting on the relationship between cancer cells and cancer-associated fibroblasts has evolved into dynamic interplay between cancer cells and multiple tumor stromal compartments, including cancer-associated fibroblasts, the extracellular matrix, endothelial cells, mesenchymal stem cells, adipocytes, and tumor-associated macrophages. Peritoneal cavities including ascites and the omentum also form a unique environment that is highly receptive for carcinomatosis in the advanced stages of ovarian cancer. The complicated but ingeniously orchestrated stroma-mediated cancer metabolism in ovarian cancer provides great heterogeneity in tumors with chemoresistance, which makes the disease thus far difficult to cure by single stromal-targeting agents. This review will discuss the experimental and clinical evidence of the cross-talk between cancer cells and various components of tumor stroma in terms of heterogeneous chemoresistance with focal points for therapeutic intervention in ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Suh
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea.
authors.forename: Hee Seung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Boyun
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: yssong@snu.ac.kr.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D005075:Biological Evolution; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents
keywords: Chemoresistance; Metabolism; Ovarian cancer; Tumor heterogeneity; Tumor microenvironments