Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism
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 mecha...
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| Veröffentlicht in: | PloS one 2014-01, Vol.9 (1), p.e84941 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0084941 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084941</identifier><identifier>PMID: 24409314</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aldehyde dehydrogenase ; Aldehyde Dehydrogenase - metabolism ; Allografts ; Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Ascites ; Biology ; Cancer ; Cancer metastasis ; Cell culture ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell Movement - genetics ; Cell Proliferation ; Cell self-renewal ; Cell Transformation, Neoplastic - metabolism ; Chemoresistance ; Chemotherapy ; Development and progression ; Disease Models, Animal ; Drug resistance ; Drug Resistance, Neoplasm ; Female ; Forming ; Gene expression ; Glucose ; Glucose metabolism ; Glycolysis ; Growth factors ; Health aspects ; Humans ; Hypoxia ; Hypoxia - metabolism ; Immunocompromised Host ; Immunology ; Immunotherapy ; Medicine ; Metabolism ; Metastases ; Metastasis ; Neoplasm Metastasis ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Oncology ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Pentose ; Routing ; Spheroids ; Spheroids, Cellular ; Stem cell transplantation ; Stem cells ; Surgery ; Tumor Burden - drug effects ; Tumor Burden - genetics ; Tumor Burden - immunology ; Tumor cell lines ; Tumor cells ; Tumor Cells, Cultured ; Tumorigenesis ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>PloS one, 2014-01, Vol.9 (1), p.e84941</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Liao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Liao et al 2014 Liao et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-516c4a534eec53335d24307202fdbfd54f2e128abaaef85bbe774259f91f51223</citedby><cites>FETCH-LOGICAL-c692t-516c4a534eec53335d24307202fdbfd54f2e128abaaef85bbe774259f91f51223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883678/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883678/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24409314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Jianqun</creatorcontrib><creatorcontrib>Qian, Feng</creatorcontrib><creatorcontrib>Tchabo, Nana</creatorcontrib><creatorcontrib>Mhawech-Fauceglia, Paulette</creatorcontrib><creatorcontrib>Beck, Amy</creatorcontrib><creatorcontrib>Qian, Zikun</creatorcontrib><creatorcontrib>Wang, Xinhui</creatorcontrib><creatorcontrib>Huss, Wendy J</creatorcontrib><creatorcontrib>Lele, Shashikant B</creatorcontrib><creatorcontrib>Morrison, Carl D</creatorcontrib><creatorcontrib>Odunsi, Kunle</creatorcontrib><title>Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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. 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metabolism</subject><subject>Immunocompromised Host</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Neoplasm Metastasis</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Oncology</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Pentose</subject><subject>Routing</subject><subject>Spheroids</subject><subject>Spheroids, Cellular</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Surgery</subject><subject>Tumor Burden - drug effects</subject><subject>Tumor Burden - 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metabolism</topic><topic>Immunocompromised Host</topic><topic>Immunology</topic><topic>Immunotherapy</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Neoplasm Metastasis</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Oncology</topic><topic>Ovarian cancer</topic><topic>Ovarian carcinoma</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Pentose</topic><topic>Routing</topic><topic>Spheroids</topic><topic>Spheroids, Cellular</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Surgery</topic><topic>Tumor Burden - drug effects</topic><topic>Tumor Burden - genetics</topic><topic>Tumor Burden - immunology</topic><topic>Tumor cell lines</topic><topic>Tumor cells</topic><topic>Tumor Cells, Cultured</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liao, Jianqun</creatorcontrib><creatorcontrib>Qian, Feng</creatorcontrib><creatorcontrib>Tchabo, Nana</creatorcontrib><creatorcontrib>Mhawech-Fauceglia, Paulette</creatorcontrib><creatorcontrib>Beck, Amy</creatorcontrib><creatorcontrib>Qian, Zikun</creatorcontrib><creatorcontrib>Wang, Xinhui</creatorcontrib><creatorcontrib>Huss, Wendy J</creatorcontrib><creatorcontrib>Lele, Shashikant B</creatorcontrib><creatorcontrib>Morrison, Carl D</creatorcontrib><creatorcontrib>Odunsi, Kunle</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liao, Jianqun</au><au>Qian, Feng</au><au>Tchabo, Nana</au><au>Mhawech-Fauceglia, Paulette</au><au>Beck, Amy</au><au>Qian, Zikun</au><au>Wang, Xinhui</au><au>Huss, Wendy J</au><au>Lele, Shashikant B</au><au>Morrison, Carl D</au><au>Odunsi, Kunle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-01-07</date><risdate>2014</risdate><volume>9</volume><issue>1</issue><spage>e84941</spage><pages>e84941-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24409314</pmid><doi>10.1371/journal.pone.0084941</doi><tpages>e84941</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-01, Vol.9 (1), p.e84941 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1475119784 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Aldehyde dehydrogenase Aldehyde Dehydrogenase - metabolism Allografts Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Ascites Biology Cancer Cancer metastasis Cell culture Cell Line, Tumor Cell migration Cell Movement - drug effects Cell Movement - genetics Cell Proliferation Cell self-renewal Cell Transformation, Neoplastic - metabolism Chemoresistance Chemotherapy Development and progression Disease Models, Animal Drug resistance Drug Resistance, Neoplasm Female Forming Gene expression Glucose Glucose metabolism Glycolysis Growth factors Health aspects Humans Hypoxia Hypoxia - metabolism Immunocompromised Host Immunology Immunotherapy Medicine Metabolism Metastases Metastasis Neoplasm Metastasis Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Oncology Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Pentose Routing Spheroids Spheroids, Cellular Stem cell transplantation Stem cells Surgery Tumor Burden - drug effects Tumor Burden - genetics Tumor Burden - immunology Tumor cell lines Tumor cells Tumor Cells, Cultured Tumorigenesis Tumors Xenograft Model Antitumor Assays |
| title | Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism |
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