CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome
Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis format...
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| Veröffentlicht in: | Journal of bone and mineral research 2013-04, Vol.28 (4), p.838-847 |
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| container_title | Journal of bone and mineral research |
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| creator | Gvozdenovic, Ana Arlt, Matthias JE Campanile, Carmen Brennecke, Patrick Husmann, Knut Li, Yufei Born, Walter Muff, Roman Fuchs, Bruno |
| description | Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p |
| doi_str_mv | 10.1002/jbmr.1817 |
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Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.</description><identifier>ISSN: 0884-0431</identifier><identifier>EISSN: 1523-4681</identifier><identifier>DOI: 10.1002/jbmr.1817</identifier><identifier>PMID: 23169460</identifier><identifier>CODEN: JBMREJ</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adolescent ; Adult ; Animals ; Carcinogenesis - metabolism ; Carcinogenesis - pathology ; CD44 ; Cell Adhesion - drug effects ; Cell Line, Tumor ; Cell Movement - drug effects ; CHEMORESISTANCE ; Child ; Drug Resistance, Neoplasm - drug effects ; Female ; Humans ; HYALURONAN ; Hyaluronan Receptors - metabolism ; Hyaluronic Acid - pharmacology ; Kaplan-Meier Estimate ; Lung Neoplasms - metabolism ; Lung Neoplasms - secondary ; Male ; METASTASIS ; Mice, SCID ; Middle Aged ; OSTEOSARCOMA ; Osteosarcoma - metabolism ; Osteosarcoma - pathology ; Prognosis ; Tibia - drug effects ; Tibia - pathology ; Treatment Outcome ; Xenograft Model Antitumor Assays ; Young Adult</subject><ispartof>Journal of bone and mineral research, 2013-04, Vol.28 (4), p.838-847</ispartof><rights>Copyright © 2013 American Society for Bone and Mineral Research</rights><rights>Copyright © 2013 American Society for Bone and Mineral Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4217-99f3098190db48b731e6a3d940de514beca6b143cd30c39bbd65a3972cf3c6f43</citedby><cites>FETCH-LOGICAL-c4217-99f3098190db48b731e6a3d940de514beca6b143cd30c39bbd65a3972cf3c6f43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjbmr.1817$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjbmr.1817$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23169460$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gvozdenovic, Ana</creatorcontrib><creatorcontrib>Arlt, Matthias JE</creatorcontrib><creatorcontrib>Campanile, Carmen</creatorcontrib><creatorcontrib>Brennecke, Patrick</creatorcontrib><creatorcontrib>Husmann, Knut</creatorcontrib><creatorcontrib>Li, Yufei</creatorcontrib><creatorcontrib>Born, Walter</creatorcontrib><creatorcontrib>Muff, Roman</creatorcontrib><creatorcontrib>Fuchs, Bruno</creatorcontrib><title>CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome</title><title>Journal of bone and mineral research</title><addtitle>J Bone Miner Res</addtitle><description>Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Animals</subject><subject>Carcinogenesis - metabolism</subject><subject>Carcinogenesis - pathology</subject><subject>CD44</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>CHEMORESISTANCE</subject><subject>Child</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>HYALURONAN</subject><subject>Hyaluronan Receptors - metabolism</subject><subject>Hyaluronic Acid - pharmacology</subject><subject>Kaplan-Meier Estimate</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - secondary</subject><subject>Male</subject><subject>METASTASIS</subject><subject>Mice, SCID</subject><subject>Middle Aged</subject><subject>OSTEOSARCOMA</subject><subject>Osteosarcoma - metabolism</subject><subject>Osteosarcoma - pathology</subject><subject>Prognosis</subject><subject>Tibia - drug effects</subject><subject>Tibia - pathology</subject><subject>Treatment Outcome</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Young Adult</subject><issn>0884-0431</issn><issn>1523-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1q3TAQRkVpaW7TLvoCRdBNu3AysmRZWqY3P01IKYR0bWRp3PpiW45k0-QF-tyR702yCAQKYrQ534GZj5CPDA4YQH64qftwwBQrX5EVK3KeCanYa7ICpUQGgrM98i7GDQDIQsq3ZC_nTGohYUX-rY-FoDj8MYPFSKe594E2PvRmav1AzeBoNw-_aY-Tiem1kbYDxdsRQ9vjMJmO-jihjyZY35ttIDEmRZ1rF0cixoCutdPOTEe_jORPcernKeXwPXnTmC7ih4d_n_w6Pblef88uf56dr48uMytyVmZaNxy0YhpcLVRdcobScKcFOCyYqNEaWTPBreNgua5rJwvDdZnbhlvZCL5Pvuy8Y_A3M8ap6ttosevMgH6OFeNCCZ1u-D8oU6DzQvOEfn6Gbvwc0uZbqpSgJahEfd1RNvgYAzbVmG5owl3FoFp6rJYeq6XHxH56MM51j-6JfCwuAYc74G_b4d3Lpuri24-rrfIe16aowA</recordid><startdate>201304</startdate><enddate>201304</enddate><creator>Gvozdenovic, Ana</creator><creator>Arlt, Matthias JE</creator><creator>Campanile, Carmen</creator><creator>Brennecke, Patrick</creator><creator>Husmann, Knut</creator><creator>Li, Yufei</creator><creator>Born, Walter</creator><creator>Muff, Roman</creator><creator>Fuchs, Bruno</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley Subscription Services, 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>7QP</scope><scope>7TS</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201304</creationdate><title>CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome</title><author>Gvozdenovic, Ana ; Arlt, Matthias JE ; Campanile, Carmen ; Brennecke, Patrick ; Husmann, Knut ; Li, Yufei ; Born, Walter ; Muff, Roman ; Fuchs, Bruno</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4217-99f3098190db48b731e6a3d940de514beca6b143cd30c39bbd65a3972cf3c6f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Animals</topic><topic>Carcinogenesis - metabolism</topic><topic>Carcinogenesis - pathology</topic><topic>CD44</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>CHEMORESISTANCE</topic><topic>Child</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>HYALURONAN</topic><topic>Hyaluronan Receptors - metabolism</topic><topic>Hyaluronic Acid - pharmacology</topic><topic>Kaplan-Meier Estimate</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - secondary</topic><topic>Male</topic><topic>METASTASIS</topic><topic>Mice, SCID</topic><topic>Middle Aged</topic><topic>OSTEOSARCOMA</topic><topic>Osteosarcoma - metabolism</topic><topic>Osteosarcoma - pathology</topic><topic>Prognosis</topic><topic>Tibia - drug effects</topic><topic>Tibia - pathology</topic><topic>Treatment Outcome</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gvozdenovic, Ana</creatorcontrib><creatorcontrib>Arlt, Matthias JE</creatorcontrib><creatorcontrib>Campanile, Carmen</creatorcontrib><creatorcontrib>Brennecke, Patrick</creatorcontrib><creatorcontrib>Husmann, Knut</creatorcontrib><creatorcontrib>Li, Yufei</creatorcontrib><creatorcontrib>Born, Walter</creatorcontrib><creatorcontrib>Muff, Roman</creatorcontrib><creatorcontrib>Fuchs, Bruno</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of bone and mineral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gvozdenovic, Ana</au><au>Arlt, Matthias JE</au><au>Campanile, Carmen</au><au>Brennecke, Patrick</au><au>Husmann, Knut</au><au>Li, Yufei</au><au>Born, Walter</au><au>Muff, Roman</au><au>Fuchs, Bruno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome</atitle><jtitle>Journal of bone and mineral research</jtitle><addtitle>J Bone Miner Res</addtitle><date>2013-04</date><risdate>2013</risdate><volume>28</volume><issue>4</issue><spage>838</spage><epage>847</epage><pages>838-847</pages><issn>0884-0431</issn><eissn>1523-4681</eissn><coden>JBMREJ</coden><abstract>Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>23169460</pmid><doi>10.1002/jbmr.1817</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current) |
| subjects | Adolescent Adult Animals Carcinogenesis - metabolism Carcinogenesis - pathology CD44 Cell Adhesion - drug effects Cell Line, Tumor Cell Movement - drug effects CHEMORESISTANCE Child Drug Resistance, Neoplasm - drug effects Female Humans HYALURONAN Hyaluronan Receptors - metabolism Hyaluronic Acid - pharmacology Kaplan-Meier Estimate Lung Neoplasms - metabolism Lung Neoplasms - secondary Male METASTASIS Mice, SCID Middle Aged OSTEOSARCOMA Osteosarcoma - metabolism Osteosarcoma - pathology Prognosis Tibia - drug effects Tibia - pathology Treatment Outcome Xenograft Model Antitumor Assays Young Adult |
| title | CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome |
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