Abstract
Survival rate in ovarian cancer has not improved since chemotherapy was introduced a few decades ago. The dismal prognosis is mostly due to disease recurrence where majority of the patients succumb to the disease. The demonstration that tumors are comprised of subfractions of cancer cells displaying heterogeneity in stemness potential, chemoresistance, and tumor repair capacity suggests that recurrence may be driven by the chemoresistant cancer stem cells. Thus to improve patient survival, novel therapies should eradicate this cancer cell population. We show that in contrast to the more differentiated ovarian cancer cells, the putative CD44+/MyD88+ ovarian cancer stem cells express lower levels of pyruvate dehydrogenase, Cox-I, Cox-II, and Cox-IV, and higher levels of UCP2. Together, this molecular phenotype establishes a bioenergetic profile that prefers the use of glycolysis over oxidative phosphorylation to generate ATP. This bioenergetic profile is conserved in vivo and therefore a maintenance regimen of 2-deoxyglucose administered after Paclitaxel treatment is able to delay the progression of recurrent tumors and decrease tumor burden in mice. Our findings strongly suggest the value of maintenance with glycolysis inhibitors with the goal of improving survival in ovarian cancer patients.
Highlights
Epithelial ovarian cancer (EOC) accounts for the greatest number of deaths from gynecologic malignancies [1,2,3]
We show in this study that in ovarian cancer, heterogeneity is exemplified by tumor-initiating potential or responsiveness to chemotherapy
The more chemoresponsive CD44-/MyD88- EOC cells require glucose for sustained proliferation but these differentiated cells can switch to oxidative phosphorylation (OXPHOS) under glucose limiting conditions
Summary
Epithelial ovarian cancer (EOC) accounts for the greatest number of deaths from gynecologic malignancies [1,2,3]. A newly diagnosed patient commonly presents with advanced-stage disease but usually undergoes remission after initial surgical debulking and first-line chemotherapy. In spite of the initial response to treatment, almost all patients recur within 2 to 5 years [4]. The development of resistance to most of the currently available agents limits the efficacy of second round chemotherapy. The five-year survival rate for EOC remains very low at about 30% [4]. To improve survival, it is necessary to identify novel treatment modalities that can prevent recurrence or target chemoresistant recurrent disease
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