Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down‐regulation and p16 overexpression inhibit cell growth in vitro
Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in...
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| creator | Schrage, Yvonne M. Lam, Suzanne Jochemsen, Aart G. Cleton‐Jansen, Anne‐Marie Taminiau, Antonie H.M. Hogendoorn, Pancras C.W. Bovée, Judith V.M.G. |
| description | Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c‐MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c‐MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high‐grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high‐grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high‐grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high‐grade chondrosarcoma. |
| doi_str_mv | 10.1111/j.1582-4934.2008.00406.x |
| format | Article |
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Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c‐MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c‐MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high‐grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high‐grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high‐grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high‐grade chondrosarcoma.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/j.1582-4934.2008.00406.x</identifier><identifier>PMID: 18624751</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; bone tumour ; c-Myc protein ; Cancer ; Cell cycle ; Cell Line, Tumor ; Cell lines ; Cell Proliferation ; Cell survival ; Cell viability ; Cells ; Chemotherapy ; Child ; Chondrosarcoma ; Chondrosarcoma - genetics ; Chondrosarcoma - metabolism ; Chondrosarcoma - pathology ; Cyclin D1 ; Cyclin-dependent kinase 4 ; Cyclin-Dependent Kinase 4 - genetics ; Cyclin-Dependent Kinase 4 - metabolism ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Cyclin-Dependent Kinase Inhibitor p16 - metabolism ; Cyclin-dependent kinase inhibitor p21 ; Disease Progression ; Down-Regulation - genetics ; Expression vectors ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Humans ; Immunohistochemistry ; Male ; MDM2 protein ; Metastases ; Metastasis ; Middle Aged ; mRNA ; Myc protein ; p53 Protein ; pRb‐pathway ; Proteins ; Proto-Oncogene Proteins c-mdm2 - genetics ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Radiation therapy ; Retinoblastoma Protein - metabolism ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; shRNA ; Signal Transduction ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Young Adult</subject><ispartof>Journal of cellular and molecular medicine, 2009-09, Vol.13 (9a), p.2843-2852</ispartof><rights>2008 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd</rights><rights>Copyright Blackwell Publishing Ltd. Sep 2009</rights><rights>2009. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2008 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5286-87a8624343086d8faf377865594e0cd8e7c4ba2457f2eca02021529accb761063</citedby><cites>FETCH-LOGICAL-c5286-87a8624343086d8faf377865594e0cd8e7c4ba2457f2eca02021529accb761063</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/PMC4498940/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498940/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2Fj.1582-4934.2008.00406.x$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18624751$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schrage, Yvonne M.</creatorcontrib><creatorcontrib>Lam, Suzanne</creatorcontrib><creatorcontrib>Jochemsen, Aart G.</creatorcontrib><creatorcontrib>Cleton‐Jansen, Anne‐Marie</creatorcontrib><creatorcontrib>Taminiau, Antonie H.M.</creatorcontrib><creatorcontrib>Hogendoorn, Pancras C.W.</creatorcontrib><creatorcontrib>Bovée, Judith V.M.G.</creatorcontrib><title>Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down‐regulation and p16 overexpression inhibit cell growth in vitro</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c‐MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c‐MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high‐grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high‐grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high‐grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high‐grade chondrosarcoma.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>bone tumour</subject><subject>c-Myc protein</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell Proliferation</subject><subject>Cell survival</subject><subject>Cell viability</subject><subject>Cells</subject><subject>Chemotherapy</subject><subject>Child</subject><subject>Chondrosarcoma</subject><subject>Chondrosarcoma - genetics</subject><subject>Chondrosarcoma - metabolism</subject><subject>Chondrosarcoma - pathology</subject><subject>Cyclin D1</subject><subject>Cyclin-dependent kinase 4</subject><subject>Cyclin-Dependent Kinase 4 - genetics</subject><subject>Cyclin-Dependent Kinase 4 - metabolism</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Disease Progression</subject><subject>Down-Regulation - genetics</subject><subject>Expression vectors</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>MDM2 protein</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>mRNA</subject><subject>Myc protein</subject><subject>p53 Protein</subject><subject>pRb‐pathway</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-mdm2 - genetics</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Radiation therapy</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - 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genetics</topic><topic>Chondrosarcoma - metabolism</topic><topic>Chondrosarcoma - pathology</topic><topic>Cyclin D1</topic><topic>Cyclin-dependent kinase 4</topic><topic>Cyclin-Dependent Kinase 4 - genetics</topic><topic>Cyclin-Dependent Kinase 4 - metabolism</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Disease Progression</topic><topic>Down-Regulation - genetics</topic><topic>Expression vectors</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Male</topic><topic>MDM2 protein</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>mRNA</topic><topic>Myc protein</topic><topic>p53 Protein</topic><topic>pRb‐pathway</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-mdm2 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Schrage, Yvonne M.</au><au>Lam, Suzanne</au><au>Jochemsen, Aart G.</au><au>Cleton‐Jansen, Anne‐Marie</au><au>Taminiau, Antonie H.M.</au><au>Hogendoorn, Pancras C.W.</au><au>Bovée, Judith V.M.G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down‐regulation and p16 overexpression inhibit cell growth in vitro</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><addtitle>J Cell Mol Med</addtitle><date>2009-09</date><risdate>2009</risdate><volume>13</volume><issue>9a</issue><spage>2843</spage><epage>2852</epage><pages>2843-2852</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><abstract>Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c‐MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c‐MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high‐grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high‐grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high‐grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high‐grade chondrosarcoma.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>18624751</pmid><doi>10.1111/j.1582-4934.2008.00406.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1582-1838 |
| ispartof | Journal of cellular and molecular medicine, 2009-09, Vol.13 (9a), p.2843-2852 |
| issn | 1582-1838 1582-4934 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4498940 |
| source | Wiley-Blackwell Open Access Titles |
| subjects | Adolescent Adult Aged Aged, 80 and over bone tumour c-Myc protein Cancer Cell cycle Cell Line, Tumor Cell lines Cell Proliferation Cell survival Cell viability Cells Chemotherapy Child Chondrosarcoma Chondrosarcoma - genetics Chondrosarcoma - metabolism Chondrosarcoma - pathology Cyclin D1 Cyclin-dependent kinase 4 Cyclin-Dependent Kinase 4 - genetics Cyclin-Dependent Kinase 4 - metabolism Cyclin-Dependent Kinase Inhibitor p16 - genetics Cyclin-Dependent Kinase Inhibitor p16 - metabolism Cyclin-dependent kinase inhibitor p21 Disease Progression Down-Regulation - genetics Expression vectors Female Gene expression Gene Expression Regulation, Neoplastic Genes Humans Immunohistochemistry Male MDM2 protein Metastases Metastasis Middle Aged mRNA Myc protein p53 Protein pRb‐pathway Proteins Proto-Oncogene Proteins c-mdm2 - genetics Proto-Oncogene Proteins c-mdm2 - metabolism Radiation therapy Retinoblastoma Protein - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism shRNA Signal Transduction Tumor Suppressor Protein p53 - metabolism Tumors Young Adult |
| title | Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down‐regulation and p16 overexpression inhibit cell growth in vitro |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T16%3A55%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_24P&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Central%20chondrosarcoma%20progression%20is%20associated%20with%20pRb%20pathway%20alterations:%20CDK4%20down%E2%80%90regulation%20and%20p16%20overexpression%20inhibit%20cell%20growth%20in%20vitro&rft.jtitle=Journal%20of%20cellular%20and%20molecular%20medicine&rft.au=Schrage,%20Yvonne%20M.&rft.date=2009-09&rft.volume=13&rft.issue=9a&rft.spage=2843&rft.epage=2852&rft.pages=2843-2852&rft.issn=1582-1838&rft.eissn=1582-4934&rft_id=info:doi/10.1111/j.1582-4934.2008.00406.x&rft_dat=%3Cproquest_24P%3E1921516121%3C/proquest_24P%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3073383151&rft_id=info:pmid/18624751&rfr_iscdi=true |