EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells
Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, an...
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| creator | Abhold, Eric L Kiang, Alan Rahimy, Elham Kuo, Selena Z Wang-Rodriguez, Jessica Lopez, Jay Patrick Blair, Katherine J Yu, Michael Andrew Haas, Martin Brumund, Kevin T Altuna, Xabier Patel, Andrew Weisman, Robert A Ongkeko, Weg M |
| description | Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC. |
| doi_str_mv | 10.1371/journal.pone.0032459 |
| format | Article |
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The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0032459</identifier><identifier>PMID: 22384257</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Antineoplastic Agents - pharmacology ; Biology ; Biotechnology ; Bmi protein ; Body mass ; Cancer ; Cancer metastasis ; Carcinoma, Squamous Cell - metabolism ; CD44 antigen ; Cell culture ; Cell growth ; Cell Line, Tumor ; Cell Proliferation ; Cell survival ; Chemotherapy ; Cisplatin ; Cisplatin - pharmacology ; CXCR4 protein ; Deregulation ; Drug development ; Drug resistance ; Ectopic expression ; Enzyme inhibitors ; Epidermal growth factor ; Epidermal growth factor receptors ; ErbB protein ; Flow Cytometry - methods ; Gefitinib ; Gene expression ; Head & neck cancer ; Head and neck cancer ; Head and Neck Neoplasms - metabolism ; Humans ; Hyaluronan Receptors - biosynthesis ; Kinases ; Medical prognosis ; Medicine ; Metastases ; Neoplasm Invasiveness ; Neoplastic Stem Cells - cytology ; Oct-4 protein ; Otolaryngology ; Quinazolines - pharmacology ; Receptor, Epidermal Growth Factor - metabolism ; Rodents ; SDF-1 protein ; Signal Transduction ; Squamous cell carcinoma ; Stem cells ; Surgery ; Therapeutic applications ; Transcription factors ; Tumorigenesis ; Tumors ; Tyrosine</subject><ispartof>PloS one, 2012-02, Vol.7 (2), p.e32459-e32459</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Abhold et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>Abhold et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-17c09bd1d56229b81c50b0262a7d32d6aed7a688ae78df7b9900af6a530b61833</citedby><cites>FETCH-LOGICAL-c691t-17c09bd1d56229b81c50b0262a7d32d6aed7a688ae78df7b9900af6a530b61833</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/PMC3288103/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288103/$$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/22384257$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abhold, Eric L</creatorcontrib><creatorcontrib>Kiang, Alan</creatorcontrib><creatorcontrib>Rahimy, Elham</creatorcontrib><creatorcontrib>Kuo, Selena Z</creatorcontrib><creatorcontrib>Wang-Rodriguez, Jessica</creatorcontrib><creatorcontrib>Lopez, Jay Patrick</creatorcontrib><creatorcontrib>Blair, Katherine J</creatorcontrib><creatorcontrib>Yu, Michael Andrew</creatorcontrib><creatorcontrib>Haas, Martin</creatorcontrib><creatorcontrib>Brumund, Kevin T</creatorcontrib><creatorcontrib>Altuna, Xabier</creatorcontrib><creatorcontrib>Patel, Andrew</creatorcontrib><creatorcontrib>Weisman, Robert A</creatorcontrib><creatorcontrib>Ongkeko, Weg M</creatorcontrib><title>EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. 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Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.</description><subject>Activation</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Bmi protein</subject><subject>Body mass</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>CD44 antigen</subject><subject>Cell culture</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell survival</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Cisplatin - pharmacology</subject><subject>CXCR4 protein</subject><subject>Deregulation</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Ectopic expression</subject><subject>Enzyme inhibitors</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB protein</subject><subject>Flow Cytometry - methods</subject><subject>Gefitinib</subject><subject>Gene expression</subject><subject>Head & neck cancer</subject><subject>Head and neck cancer</subject><subject>Head and Neck Neoplasms - metabolism</subject><subject>Humans</subject><subject>Hyaluronan Receptors - biosynthesis</subject><subject>Kinases</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Metastases</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Oct-4 protein</subject><subject>Otolaryngology</subject><subject>Quinazolines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Rodents</subject><subject>SDF-1 protein</subject><subject>Signal Transduction</subject><subject>Squamous cell carcinoma</subject><subject>Stem 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Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</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>Abhold, Eric L</au><au>Kiang, Alan</au><au>Rahimy, Elham</au><au>Kuo, Selena Z</au><au>Wang-Rodriguez, Jessica</au><au>Lopez, Jay Patrick</au><au>Blair, Katherine J</au><au>Yu, Michael Andrew</au><au>Haas, Martin</au><au>Brumund, Kevin T</au><au>Altuna, Xabier</au><au>Patel, Andrew</au><au>Weisman, Robert A</au><au>Ongkeko, Weg M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-02-27</date><risdate>2012</risdate><volume>7</volume><issue>2</issue><spage>e32459</spage><epage>e32459</epage><pages>e32459-e32459</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22384257</pmid><doi>10.1371/journal.pone.0032459</doi><tpages>e32459</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-02, Vol.7 (2), p.e32459-e32459 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1333201070 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Antineoplastic Agents - pharmacology Biology Biotechnology Bmi protein Body mass Cancer Cancer metastasis Carcinoma, Squamous Cell - metabolism CD44 antigen Cell culture Cell growth Cell Line, Tumor Cell Proliferation Cell survival Chemotherapy Cisplatin Cisplatin - pharmacology CXCR4 protein Deregulation Drug development Drug resistance Ectopic expression Enzyme inhibitors Epidermal growth factor Epidermal growth factor receptors ErbB protein Flow Cytometry - methods Gefitinib Gene expression Head & neck cancer Head and neck cancer Head and Neck Neoplasms - metabolism Humans Hyaluronan Receptors - biosynthesis Kinases Medical prognosis Medicine Metastases Neoplasm Invasiveness Neoplastic Stem Cells - cytology Oct-4 protein Otolaryngology Quinazolines - pharmacology Receptor, Epidermal Growth Factor - metabolism Rodents SDF-1 protein Signal Transduction Squamous cell carcinoma Stem cells Surgery Therapeutic applications Transcription factors Tumorigenesis Tumors Tyrosine |
| title | EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells |
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