Abstract

Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >105 parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. 13C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy.

Highlights

  • Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies

  • We found that spheroid cells increase anaerobic glycolysis and pentose cycle and decrease re-routing of glucose for anabolic purposes

  • Spheroid cells were generated from new epithelial ovarian cancer (EOC) cell lines and from an established ovarian cancer cell line, OV2774, which were obtained from Sloan Kettering Institute, New York, NY

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Summary

Introduction

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. Despite modest improvements in response rates, progression-free and median survival using adjuvant platinum and taxane chemotherapy following cytoreductive surgery, overall survival rates for patients with advanced EOC and ovarian-like malignancies (primary peritoneal) remain disappointing [2]. This has been attributed to several reasons. In contrast to most other solid tumors, more than 75% of EOC patients present with advanced stage disease (FIGO III or IV). Within 2 years of cytoreductive surgery and systemic chemotherapy, tumors usually recur and once relapse occurs, curative therapy is difficult. It is imperative to understand the mechanism(s) of EOC metastasis and chemotherapy resistance in order to improve clinical outcomes in this disease

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