CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes
There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2018-04, Vol.78 (8), p.2026-2039 |
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| creator | Jung, Younghun Cackowski, Frank C Yumoto, Kenji Decker, Ann M Wang, Jingcheng Kim, Jin Koo Lee, Eunsohl Wang, Yugang Chung, Jae-Seung Gursky, Amy M Krebsbach, Paul H Pienta, Kenneth J Morgan, Todd M Taichman, Russell S |
| description | There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance
Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.
Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC.
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| doi_str_mv | 10.1158/0008-5472.CAN-17-2332 |
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Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.
Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC.
.</description><identifier>ISSN: 0008-5472</identifier><identifier>ISSN: 1538-7445</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-17-2332</identifier><identifier>PMID: 29431639</identifier><language>eng</language><publisher>United States: American Association for Cancer Research, Inc</publisher><subject>Animals ; Bone Neoplasms - secondary ; Castration ; Cell Line, Tumor ; Cell Proliferation - physiology ; Cellular Reprogramming ; Chemokine CXCL12 - physiology ; Chemoresistance ; CXCR4 protein ; Heterografts ; Humans ; Male ; Metastases ; Metastasis ; Mice, SCID ; Neoplastic Stem Cells - pathology ; Neuroendocrine Cells - pathology ; NF-kappa B - metabolism ; NF-κB protein ; Phenotype ; Phenotypes ; Prostate cancer ; Prostatic Neoplasms, Castration-Resistant - pathology ; Protein kinase C ; Protein Kinase C-alpha - metabolism ; Receptors, CXCR4 - metabolism ; Signal Transduction ; Stem cells ; Therapeutic applications ; Tumor cells</subject><ispartof>Cancer research (Chicago, Ill.), 2018-04, Vol.78 (8), p.2026-2039</ispartof><rights>2018 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research, Inc. Apr 15, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c366t-734b55db8745adec5391b79f53fed42b17f4e004e674dc31f7dbc36b3782087b3</citedby><cites>FETCH-LOGICAL-c366t-734b55db8745adec5391b79f53fed42b17f4e004e674dc31f7dbc36b3782087b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29431639$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jung, Younghun</creatorcontrib><creatorcontrib>Cackowski, Frank C</creatorcontrib><creatorcontrib>Yumoto, Kenji</creatorcontrib><creatorcontrib>Decker, Ann M</creatorcontrib><creatorcontrib>Wang, Jingcheng</creatorcontrib><creatorcontrib>Kim, Jin Koo</creatorcontrib><creatorcontrib>Lee, Eunsohl</creatorcontrib><creatorcontrib>Wang, Yugang</creatorcontrib><creatorcontrib>Chung, Jae-Seung</creatorcontrib><creatorcontrib>Gursky, Amy M</creatorcontrib><creatorcontrib>Krebsbach, Paul H</creatorcontrib><creatorcontrib>Pienta, Kenneth J</creatorcontrib><creatorcontrib>Morgan, Todd M</creatorcontrib><creatorcontrib>Taichman, Russell S</creatorcontrib><title>CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance
Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.
Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC.
.</description><subject>Animals</subject><subject>Bone Neoplasms - secondary</subject><subject>Castration</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - physiology</subject><subject>Cellular Reprogramming</subject><subject>Chemokine CXCL12 - physiology</subject><subject>Chemoresistance</subject><subject>CXCR4 protein</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice, SCID</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Neuroendocrine Cells - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Protein kinase C</subject><subject>Protein Kinase C-alpha - metabolism</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>Signal Transduction</subject><subject>Stem cells</subject><subject>Therapeutic applications</subject><subject>Tumor cells</subject><issn>0008-5472</issn><issn>1538-7445</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkclqHDEQhoWJiSd2HsFBkEsubWtt9RxN4ziG8YIX8E20pOqkzbQ0kdSHgbyV38PPZDVeDrlItXx_UdSP0CElR5TK5pgQ0lRSKHbUnlxWVFWMc7aDFlTyplJCyE9o8cHsoS8pPZZUUiI_oz22FJzWfLlA_9qHdkXZ8xO-jmEMGRK-gNyl3OXB4rYEsUTBVzeQhlL1eQbnNpSutxCx2eJz7yY7-N_vpdsMI25hvcadd_gSphjAu2Dj4AFf_wEf8nYD6QDt9t06wde3fx_d_zy9a39Vq6uz8_ZkVVle17lSXBgpnWmUkJ0DK_mSGrXsJe_BCWao6gUQIqBWwllOe-VMURquGkYaZfg--vE6dxPD3wlS1uOQbFmv8xCmpBkhVBDO6rqg3_9DH8MUfdmuUEywuilvoeQrZcstUoReb-IwdnGrKdGzPXo-vZ5Pr4s9mio921N0396mT2YE96F694O_AI3GjA0</recordid><startdate>20180415</startdate><enddate>20180415</enddate><creator>Jung, Younghun</creator><creator>Cackowski, Frank C</creator><creator>Yumoto, Kenji</creator><creator>Decker, Ann M</creator><creator>Wang, Jingcheng</creator><creator>Kim, Jin Koo</creator><creator>Lee, Eunsohl</creator><creator>Wang, Yugang</creator><creator>Chung, Jae-Seung</creator><creator>Gursky, Amy M</creator><creator>Krebsbach, Paul H</creator><creator>Pienta, Kenneth J</creator><creator>Morgan, Todd M</creator><creator>Taichman, Russell S</creator><general>American Association for Cancer Research, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20180415</creationdate><title>CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes</title><author>Jung, Younghun ; Cackowski, Frank C ; Yumoto, Kenji ; Decker, Ann M ; Wang, Jingcheng ; Kim, Jin Koo ; Lee, Eunsohl ; Wang, Yugang ; Chung, Jae-Seung ; Gursky, Amy M ; Krebsbach, Paul H ; Pienta, Kenneth J ; Morgan, Todd M ; Taichman, Russell S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-734b55db8745adec5391b79f53fed42b17f4e004e674dc31f7dbc36b3782087b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Bone Neoplasms - secondary</topic><topic>Castration</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - physiology</topic><topic>Cellular Reprogramming</topic><topic>Chemokine CXCL12 - physiology</topic><topic>Chemoresistance</topic><topic>CXCR4 protein</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Male</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice, SCID</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Neuroendocrine Cells - pathology</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Protein kinase C</topic><topic>Protein Kinase C-alpha - metabolism</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Signal Transduction</topic><topic>Stem cells</topic><topic>Therapeutic applications</topic><topic>Tumor cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jung, Younghun</creatorcontrib><creatorcontrib>Cackowski, Frank C</creatorcontrib><creatorcontrib>Yumoto, Kenji</creatorcontrib><creatorcontrib>Decker, Ann M</creatorcontrib><creatorcontrib>Wang, Jingcheng</creatorcontrib><creatorcontrib>Kim, Jin Koo</creatorcontrib><creatorcontrib>Lee, Eunsohl</creatorcontrib><creatorcontrib>Wang, Yugang</creatorcontrib><creatorcontrib>Chung, Jae-Seung</creatorcontrib><creatorcontrib>Gursky, Amy M</creatorcontrib><creatorcontrib>Krebsbach, Paul H</creatorcontrib><creatorcontrib>Pienta, Kenneth J</creatorcontrib><creatorcontrib>Morgan, Todd M</creatorcontrib><creatorcontrib>Taichman, Russell S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jung, Younghun</au><au>Cackowski, Frank C</au><au>Yumoto, Kenji</au><au>Decker, Ann M</au><au>Wang, Jingcheng</au><au>Kim, Jin Koo</au><au>Lee, Eunsohl</au><au>Wang, Yugang</au><au>Chung, Jae-Seung</au><au>Gursky, Amy M</au><au>Krebsbach, Paul H</au><au>Pienta, Kenneth J</au><au>Morgan, Todd M</au><au>Taichman, Russell S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2018-04-15</date><risdate>2018</risdate><volume>78</volume><issue>8</issue><spage>2026</spage><epage>2039</epage><pages>2026-2039</pages><issn>0008-5472</issn><issn>1538-7445</issn><eissn>1538-7445</eissn><abstract>There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance
Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.
Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC.
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| subjects | Animals Bone Neoplasms - secondary Castration Cell Line, Tumor Cell Proliferation - physiology Cellular Reprogramming Chemokine CXCL12 - physiology Chemoresistance CXCR4 protein Heterografts Humans Male Metastases Metastasis Mice, SCID Neoplastic Stem Cells - pathology Neuroendocrine Cells - pathology NF-kappa B - metabolism NF-κB protein Phenotype Phenotypes Prostate cancer Prostatic Neoplasms, Castration-Resistant - pathology Protein kinase C Protein Kinase C-alpha - metabolism Receptors, CXCR4 - metabolism Signal Transduction Stem cells Therapeutic applications Tumor cells |
| title | CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes |
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