Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A
Abstract Context: Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown. Objective: To define differential...
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| Veröffentlicht in: | The journal of clinical endocrinology and metabolism 2017-05, Vol.102 (5), p.1588-1595 |
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| creator | Moravek, Molly B. Yin, Ping Coon, John S. Ono, Masanori Druschitz, Stacy A. Malpani, Saurabh S. Dyson, Matthew T. Rademaker, Alfred W. Robins, Jared C. Wei, Jian-Jun Kim, J. Julie Bulun, Serdar E. |
| description | Abstract
Context:
Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown.
Objective:
To define differential gene expression and signaling pathways in leiomyoma cell populations.
Design:
Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b−. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2′-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma.
Setting:
Research laboratory.
Patients:
Eight African American women.
Interventions:
None
Main Outcomes Measures:
Gene expression patterns, cell proliferation, and differentiation.
Results:
A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b− intermediary cells, which then terminally differentiate to CD34−/CD49b− cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b− vs CD34−/CD49b− cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34−/CD49b− cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation.
Conclusions:
IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.
Microarray and functional studies of three leiomyoma cell populations, including stem cells, implicated the IGF2 pathway in paracrine signaling and as important for cell proliferation. |
| doi_str_mv | 10.1210/jc.2016-3497 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5443334</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1210/jc.2016-3497</oup_id><sourcerecordid>2030631293</sourcerecordid><originalsourceid>FETCH-LOGICAL-c510t-ec15555e4934635215f4a1be07cd4c468d42a170beef2c4ffc0fcc65e4b77b1e3</originalsourceid><addsrcrecordid>eNp1ks1rGzEQxUVpadykt56LoIf2kE1GH_t1KQTTpAFDQ9JAb0Irz9ZydyVX2nXwfx9tnIS20LkMzPzmoccTIe8YnDDO4HRtTjiwIhOyLl-QGatlnpWsLl-SGQBnWV3yHwfkTYxrACZlLl6TA14JLoHDjPRXOmgTrEN6pYfVnd5Fah29HfBhtkDr-53vNb0ZsKdz7LpIL93Wd1tMPY6ddZ39hfQi-LthRc-1GXygnGq3fNrTazS4mcZnR-RVq7uIbx_7Ibk9__J9_jVbfLu4nJ8tMpMzGDI0LE-FshayEDlneSs1axBKs5RGFtVScs1KaBBbbmTbGmiNKdJBU5YNQ3FIPu91N2PT49KgG4Lu1CbYXoed8tqqvzfOrtRPv1W5lEIImQQ-PQoE_3vEOKjeRpPca4d-jIpVFUAlq2pCP_yDrv0YXLKnOAgoBOO1SNTxnjLBxxiwfX4MAzXlqNZGTTmqKceEv__TwDP8FFwCPu4BP27-J_XwJcQ9fsulpg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2030631293</pqid></control><display><type>article</type><title>Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><source>Journals@Ovid Complete</source><source>ProQuest Central</source><creator>Moravek, Molly B. ; Yin, Ping ; Coon, John S. ; Ono, Masanori ; Druschitz, Stacy A. ; Malpani, Saurabh S. ; Dyson, Matthew T. ; Rademaker, Alfred W. ; Robins, Jared C. ; Wei, Jian-Jun ; Kim, J. Julie ; Bulun, Serdar E.</creator><creatorcontrib>Moravek, Molly B. ; Yin, Ping ; Coon, John S. ; Ono, Masanori ; Druschitz, Stacy A. ; Malpani, Saurabh S. ; Dyson, Matthew T. ; Rademaker, Alfred W. ; Robins, Jared C. ; Wei, Jian-Jun ; Kim, J. Julie ; Bulun, Serdar E.</creatorcontrib><description>Abstract
Context:
Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown.
Objective:
To define differential gene expression and signaling pathways in leiomyoma cell populations.
Design:
Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b−. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2′-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma.
Setting:
Research laboratory.
Patients:
Eight African American women.
Interventions:
None
Main Outcomes Measures:
Gene expression patterns, cell proliferation, and differentiation.
Results:
A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b− intermediary cells, which then terminally differentiate to CD34−/CD49b− cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b− vs CD34−/CD49b− cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34−/CD49b− cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation.
Conclusions:
IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.
Microarray and functional studies of three leiomyoma cell populations, including stem cells, implicated the IGF2 pathway in paracrine signaling and as important for cell proliferation.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jc.2016-3497</identifier><identifier>PMID: 28324020</identifier><language>eng</language><publisher>Washington, DC: Endocrine Society</publisher><subject>Adult ; African Americans ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Antigens, CD34 - metabolism ; CD34 antigen ; Cell Differentiation - genetics ; Cell growth ; Cell number ; Cell proliferation ; Cell Proliferation - genetics ; Clinical s ; DNA microarrays ; Extracellular signal-regulated kinase ; Female ; Fibroids ; Flow Cytometry ; Gene expression ; Gene Expression Profiling ; Growth factors ; Humans ; Immunoblotting ; Insulin ; Insulin-like growth factor I ; Insulin-like growth factor II ; Insulin-Like Growth Factor II - genetics ; Insulin-Like Growth Factor II - metabolism ; Integrin alpha2 - metabolism ; Kinases ; Leiomyoma - genetics ; Leiomyoma - metabolism ; MAP Kinase Signaling System ; Middle Aged ; Neoplastic Stem Cells - cytology ; Neoplastic Stem Cells - metabolism ; Paracrine Communication - genetics ; Paracrine signalling ; Phosphorylation ; Polymerase chain reaction ; Real-Time Polymerase Chain Reaction ; Receptor, Insulin - genetics ; Receptor, Insulin - metabolism ; Signal transduction ; Stem cells ; Tissue Array Analysis ; Tumors ; Uterine Neoplasms - genetics ; Uterine Neoplasms - metabolism ; Uterus</subject><ispartof>The journal of clinical endocrinology and metabolism, 2017-05, Vol.102 (5), p.1588-1595</ispartof><rights>Copyright © 2017 Endocrine Society 2017</rights><rights>Copyright © 2017 by the Endocrine Society</rights><rights>Copyright © 2017 Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c510t-ec15555e4934635215f4a1be07cd4c468d42a170beef2c4ffc0fcc65e4b77b1e3</citedby><cites>FETCH-LOGICAL-c510t-ec15555e4934635215f4a1be07cd4c468d42a170beef2c4ffc0fcc65e4b77b1e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2030631293?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,776,780,881,21367,27901,27902,33721,33722,43781</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28324020$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moravek, Molly B.</creatorcontrib><creatorcontrib>Yin, Ping</creatorcontrib><creatorcontrib>Coon, John S.</creatorcontrib><creatorcontrib>Ono, Masanori</creatorcontrib><creatorcontrib>Druschitz, Stacy A.</creatorcontrib><creatorcontrib>Malpani, Saurabh S.</creatorcontrib><creatorcontrib>Dyson, Matthew T.</creatorcontrib><creatorcontrib>Rademaker, Alfred W.</creatorcontrib><creatorcontrib>Robins, Jared C.</creatorcontrib><creatorcontrib>Wei, Jian-Jun</creatorcontrib><creatorcontrib>Kim, J. Julie</creatorcontrib><creatorcontrib>Bulun, Serdar E.</creatorcontrib><title>Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J Clin Endocrinol Metab</addtitle><description>Abstract
Context:
Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown.
Objective:
To define differential gene expression and signaling pathways in leiomyoma cell populations.
Design:
Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b−. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2′-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma.
Setting:
Research laboratory.
Patients:
Eight African American women.
Interventions:
None
Main Outcomes Measures:
Gene expression patterns, cell proliferation, and differentiation.
Results:
A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b− intermediary cells, which then terminally differentiate to CD34−/CD49b− cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b− vs CD34−/CD49b− cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34−/CD49b− cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation.
Conclusions:
IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.
Microarray and functional studies of three leiomyoma cell populations, including stem cells, implicated the IGF2 pathway in paracrine signaling and as important for cell proliferation.</description><subject>Adult</subject><subject>African Americans</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Antigens, CD34 - metabolism</subject><subject>CD34 antigen</subject><subject>Cell Differentiation - genetics</subject><subject>Cell growth</subject><subject>Cell number</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - genetics</subject><subject>Clinical s</subject><subject>DNA microarrays</subject><subject>Extracellular signal-regulated kinase</subject><subject>Female</subject><subject>Fibroids</subject><subject>Flow Cytometry</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Insulin</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-like growth factor II</subject><subject>Insulin-Like Growth Factor II - genetics</subject><subject>Insulin-Like Growth Factor II - metabolism</subject><subject>Integrin alpha2 - metabolism</subject><subject>Kinases</subject><subject>Leiomyoma - genetics</subject><subject>Leiomyoma - metabolism</subject><subject>MAP Kinase Signaling System</subject><subject>Middle Aged</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Paracrine Communication - genetics</subject><subject>Paracrine signalling</subject><subject>Phosphorylation</subject><subject>Polymerase chain reaction</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Receptor, Insulin - genetics</subject><subject>Receptor, Insulin - metabolism</subject><subject>Signal transduction</subject><subject>Stem cells</subject><subject>Tissue Array Analysis</subject><subject>Tumors</subject><subject>Uterine Neoplasms - genetics</subject><subject>Uterine Neoplasms - metabolism</subject><subject>Uterus</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1ks1rGzEQxUVpadykt56LoIf2kE1GH_t1KQTTpAFDQ9JAb0Irz9ZydyVX2nXwfx9tnIS20LkMzPzmoccTIe8YnDDO4HRtTjiwIhOyLl-QGatlnpWsLl-SGQBnWV3yHwfkTYxrACZlLl6TA14JLoHDjPRXOmgTrEN6pYfVnd5Fah29HfBhtkDr-53vNb0ZsKdz7LpIL93Wd1tMPY6ddZ39hfQi-LthRc-1GXygnGq3fNrTazS4mcZnR-RVq7uIbx_7Ibk9__J9_jVbfLu4nJ8tMpMzGDI0LE-FshayEDlneSs1axBKs5RGFtVScs1KaBBbbmTbGmiNKdJBU5YNQ3FIPu91N2PT49KgG4Lu1CbYXoed8tqqvzfOrtRPv1W5lEIImQQ-PQoE_3vEOKjeRpPca4d-jIpVFUAlq2pCP_yDrv0YXLKnOAgoBOO1SNTxnjLBxxiwfX4MAzXlqNZGTTmqKceEv__TwDP8FFwCPu4BP27-J_XwJcQ9fsulpg</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Moravek, Molly B.</creator><creator>Yin, Ping</creator><creator>Coon, John S.</creator><creator>Ono, Masanori</creator><creator>Druschitz, Stacy A.</creator><creator>Malpani, Saurabh S.</creator><creator>Dyson, Matthew T.</creator><creator>Rademaker, Alfred W.</creator><creator>Robins, Jared C.</creator><creator>Wei, Jian-Jun</creator><creator>Kim, J. Julie</creator><creator>Bulun, Serdar E.</creator><general>Endocrine Society</general><general>Oxford University Press</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>3V.</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170501</creationdate><title>Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A</title><author>Moravek, Molly B. ; Yin, Ping ; Coon, John S. ; Ono, Masanori ; Druschitz, Stacy A. ; Malpani, Saurabh S. ; Dyson, Matthew T. ; Rademaker, Alfred W. ; Robins, Jared C. ; Wei, Jian-Jun ; Kim, J. Julie ; Bulun, Serdar E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c510t-ec15555e4934635215f4a1be07cd4c468d42a170beef2c4ffc0fcc65e4b77b1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>African Americans</topic><topic>Antigens, CD - genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Antigens, CD34 - metabolism</topic><topic>CD34 antigen</topic><topic>Cell Differentiation - genetics</topic><topic>Cell growth</topic><topic>Cell number</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - genetics</topic><topic>Clinical s</topic><topic>DNA microarrays</topic><topic>Extracellular signal-regulated kinase</topic><topic>Female</topic><topic>Fibroids</topic><topic>Flow Cytometry</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Insulin</topic><topic>Insulin-like growth factor I</topic><topic>Insulin-like growth factor II</topic><topic>Insulin-Like Growth Factor II - genetics</topic><topic>Insulin-Like Growth Factor II - metabolism</topic><topic>Integrin alpha2 - metabolism</topic><topic>Kinases</topic><topic>Leiomyoma - genetics</topic><topic>Leiomyoma - metabolism</topic><topic>MAP Kinase Signaling System</topic><topic>Middle Aged</topic><topic>Neoplastic Stem Cells - cytology</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Paracrine Communication - genetics</topic><topic>Paracrine signalling</topic><topic>Phosphorylation</topic><topic>Polymerase chain reaction</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Receptor, Insulin - genetics</topic><topic>Receptor, Insulin - metabolism</topic><topic>Signal transduction</topic><topic>Stem cells</topic><topic>Tissue Array Analysis</topic><topic>Tumors</topic><topic>Uterine Neoplasms - genetics</topic><topic>Uterine Neoplasms - metabolism</topic><topic>Uterus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moravek, Molly B.</creatorcontrib><creatorcontrib>Yin, Ping</creatorcontrib><creatorcontrib>Coon, John S.</creatorcontrib><creatorcontrib>Ono, Masanori</creatorcontrib><creatorcontrib>Druschitz, Stacy A.</creatorcontrib><creatorcontrib>Malpani, Saurabh S.</creatorcontrib><creatorcontrib>Dyson, Matthew T.</creatorcontrib><creatorcontrib>Rademaker, Alfred W.</creatorcontrib><creatorcontrib>Robins, Jared C.</creatorcontrib><creatorcontrib>Wei, Jian-Jun</creatorcontrib><creatorcontrib>Kim, J. Julie</creatorcontrib><creatorcontrib>Bulun, Serdar E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moravek, Molly B.</au><au>Yin, Ping</au><au>Coon, John S.</au><au>Ono, Masanori</au><au>Druschitz, Stacy A.</au><au>Malpani, Saurabh S.</au><au>Dyson, Matthew T.</au><au>Rademaker, Alfred W.</au><au>Robins, Jared C.</au><au>Wei, Jian-Jun</au><au>Kim, J. Julie</au><au>Bulun, Serdar E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>102</volume><issue>5</issue><spage>1588</spage><epage>1595</epage><pages>1588-1595</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><abstract>Abstract
Context:
Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown.
Objective:
To define differential gene expression and signaling pathways in leiomyoma cell populations.
Design:
Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b−. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2′-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma.
Setting:
Research laboratory.
Patients:
Eight African American women.
Interventions:
None
Main Outcomes Measures:
Gene expression patterns, cell proliferation, and differentiation.
Results:
A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b− intermediary cells, which then terminally differentiate to CD34−/CD49b− cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b− vs CD34−/CD49b− cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34−/CD49b− cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation.
Conclusions:
IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.
Microarray and functional studies of three leiomyoma cell populations, including stem cells, implicated the IGF2 pathway in paracrine signaling and as important for cell proliferation.</abstract><cop>Washington, DC</cop><pub>Endocrine Society</pub><pmid>28324020</pmid><doi>10.1210/jc.2016-3497</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-972X |
| ispartof | The journal of clinical endocrinology and metabolism, 2017-05, Vol.102 (5), p.1588-1595 |
| issn | 0021-972X 1945-7197 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5443334 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Journals@Ovid Complete; ProQuest Central |
| subjects | Adult African Americans Antigens, CD - genetics Antigens, CD - metabolism Antigens, CD34 - metabolism CD34 antigen Cell Differentiation - genetics Cell growth Cell number Cell proliferation Cell Proliferation - genetics Clinical s DNA microarrays Extracellular signal-regulated kinase Female Fibroids Flow Cytometry Gene expression Gene Expression Profiling Growth factors Humans Immunoblotting Insulin Insulin-like growth factor I Insulin-like growth factor II Insulin-Like Growth Factor II - genetics Insulin-Like Growth Factor II - metabolism Integrin alpha2 - metabolism Kinases Leiomyoma - genetics Leiomyoma - metabolism MAP Kinase Signaling System Middle Aged Neoplastic Stem Cells - cytology Neoplastic Stem Cells - metabolism Paracrine Communication - genetics Paracrine signalling Phosphorylation Polymerase chain reaction Real-Time Polymerase Chain Reaction Receptor, Insulin - genetics Receptor, Insulin - metabolism Signal transduction Stem cells Tissue Array Analysis Tumors Uterine Neoplasms - genetics Uterine Neoplasms - metabolism Uterus |
| title | Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T14%3A30%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Paracrine%20Pathways%20in%20Uterine%20Leiomyoma%20Stem%20Cells%20Involve%20Insulinlike%20Growth%20Factor%202%20and%20Insulin%20Receptor%20A&rft.jtitle=The%20journal%20of%20clinical%20endocrinology%20and%20metabolism&rft.au=Moravek,%20Molly%20B.&rft.date=2017-05-01&rft.volume=102&rft.issue=5&rft.spage=1588&rft.epage=1595&rft.pages=1588-1595&rft.issn=0021-972X&rft.eissn=1945-7197&rft_id=info:doi/10.1210/jc.2016-3497&rft_dat=%3Cproquest_pubme%3E2030631293%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2030631293&rft_id=info:pmid/28324020&rft_oup_id=10.1210/jc.2016-3497&rfr_iscdi=true |