Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism

Jianqun Liao, Feng Qian, Nana Tchabo, Paulette Mhawech-Fauceglia, Amy Beck, Zikun Qian, Xinhui Wang, Wendy J. Huss, Shashikant B. Lele, Carl D. Morrison, Kunle Odunsi

Research output: Contribution to journalArticle

154 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere84941
JournalPLoS ONE
Volume9
Issue number1
DOIs
StatePublished - Jan 7 2014
Externally publishedYes

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Chemotherapy
ovarian neoplasms
Stem cells
Metabolism
metastasis
Ovarian Neoplasms
drug therapy
stem cells
Tumors
hypoxia
Stem Cells
Neoplasm Metastasis
Drug Therapy
neoplasms
metabolism
Neoplasms
Glucose
cells
Cells
Neoplastic Stem Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Liao, Jianqun ; Qian, Feng ; Tchabo, Nana ; Mhawech-Fauceglia, Paulette ; Beck, Amy ; Qian, Zikun ; Wang, Xinhui ; Huss, Wendy J. ; Lele, Shashikant B. ; Morrison, Carl D. ; Odunsi, Kunle. / Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. In: PLoS ONE. 2014 ; Vol. 9, No. 1.
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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.",
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Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. / Liao, Jianqun; Qian, Feng; Tchabo, Nana; Mhawech-Fauceglia, Paulette; Beck, Amy; Qian, Zikun; Wang, Xinhui; Huss, Wendy J.; Lele, Shashikant B.; Morrison, Carl D.; Odunsi, Kunle.

In: PLoS ONE, Vol. 9, No. 1, e84941, 07.01.2014.

Research output: Contribution to journalArticle

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AU - Liao, Jianqun

AU - Qian, Feng

AU - Tchabo, Nana

AU - Mhawech-Fauceglia, Paulette

AU - Beck, Amy

AU - Qian, Zikun

AU - Wang, Xinhui

AU - Huss, Wendy J.

AU - Lele, Shashikant B.

AU - Morrison, Carl D.

AU - Odunsi, Kunle

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Y1 - 2014/1/7

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