title: Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism.
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 >10(5) 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. (13)C-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.
authors.affiliation: Departments of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America ; Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Jianqun
authors.initials: J
authors.lastname: Liao
authors.affiliation: Immunology; Roswell Park Cancer Institute, Buffalo, New York, United States of America ; Center for Immunotherapy; Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: Atlantic Health System Morristown/Overlook Medical Centers, Women's Cancer Center, Morristown and Summit, New Jersey, United States of America.
authors.forename: Nana
authors.initials: N
authors.lastname: Tchabo
authors.affiliation: Pathology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.affiliation: Center for Immunotherapy; Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Beck
authors.affiliation: Center for Immunotherapy; Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Zikun
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Urology Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America ; Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Huss
authors.affiliation: Departments of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Shashikant B
authors.initials: SB
authors.lastname: Lele
authors.affiliation: Pathology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
authors.affiliation: Departments of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America ; Immunology; Roswell Park Cancer Institute, Buffalo, New York, United States of America ; Center for Immunotherapy; Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D016867:Immunocompromised Host; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018874:Spheroids, Cellular; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000444:Aldehyde Dehydrogenase