Towards new therapeutic strategies in chondrosarcoma Schrage, Y.M.

Schrage, Y.M.

Citation

Schrage, Y. M. (2009, November 5). Towards new therapeutic strategies in chondrosarcoma. Retrieved from https://hdl.handle.net/1887/14327

Version: Corrected Publisher’s Version

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associated with pRb pathway alterations;

CDK4 downregulation and p16

overexpression inhibit cell growth in vitro

Yvonne M. Schrage, Suzanne Lam, Aart G. Jochemsen, Anne-Marie Cleton-Jansen, Antonie H.M Taminiau, Pancras C.W. Hogendoorn, Judith V.M.G. Bovée

J Cell Mol Med 2008; in press.

70

Abstract

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PHWDVWDWLFGLVHDVH7KHDLPRIWKLVVWXG\LVWRLQYHVWLJDWHJHQHVLQYROYHGLQ

FHOOF\FOHFRQWUROCDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c-MYC, ZKLFKPD\SRLQWWRZDUGVQHZWKHUDSHXWLFVWUDWHJLHV.7KHS5ESDWKZD\ZDV

targeted using CDKN2A/p16 RYHUH[SUHVVLQJ YHFWRUV DQG VK51$ DJDLQVW

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survival and proliferation were assessed. CDK4, MDM2 and c-MYCH[SUHVVLRQ

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2YHUH[SUHVVLRQ RI CDKN2A/p16 and knock down of CDK4 E\ VK51$

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in vitro ([SUHVVLRQ RI CDK4 and MDM2 was associated with high-grade FKRQGURVDUFRPD ERWK DW WKH P51$ DQG SURWHLQ OHYHO &RPELQLQJ WKHVH

UHVXOWVZLWKWKHH[SUHVVLRQRIcyclin D1 DQGWKHSUHYLRXVO\VKRZQORVVRI

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high-grade chondrosarcoma.

Introduction

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is notorious for its resistance to conventional chemo- and radiation WKHUDS\ 7KH PDMRULW\ RI WXPRXUV DULVH LQ WKH PHGXOODU FDYLW\ RI ERQH

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of tumours can result in local recurrence. Thirteen percent of recurrent FKRQGURVDUFRPDV DUH RI D KLJKHU JUDGH WKDQ WKH SULPDU\ WXPRXU^.

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treatment. There is no treatment to offer patients with metastatic disease or LQRSHUDEOHWXPRXUVLQWKHH[WUHPLWLHVRUSHOYLV(OXFLGDWLQJWKHPROHFXODU

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strategies to improve clinical outcome.

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DPSOLÀFDWLRQRIT^DQGGHOHWLRQRIS^7-9 are two consistent genetic DEHUUDWLRQV 8VLQJ DUUD\ &RPSDUDWLYH *HQRPLF +\EULGLVDWLRQ &*+

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chondrosarcomas, which correlated with high histological grade^, as was DOVRVXJJHVWHGE\RWKHUV⁹. Several genes in this region are of importance IRUFHOOF\FOHFRQWUROLQFOXGLQJCDK4 and MDM2SOD\HUVLQWKHS5EDQG

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mutations were not found⁵5RSNHHWDOVKRZHGS5EH[SUHVVLRQLQ

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tumour suppressor protein p53 is activated upon various forms of stress, LQFOXGLQJDEHUUDQWPLWRJHQLFVLJQDOOLQJUHVXOWLQJLQFHOOF\FOHDUUHVWDQG

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chondrosarcomas.

Materials and Methods Cell culture

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Proliferation assays

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Patient material

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Enchondromas Chondrosarcomas

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Pearson chi-square. Immunohistochemical data were correlated with follow



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Results

Functional analysis of the pRb pathway in vitro

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Table 4.2 Immunohistochemical staining of 90 FFPE samples of enchondroma and chondrosarcoma patients

pRb pathway p53 pathway

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D1 p21 MDM2 p53

   - - - QD -

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Summary 28/29 (96%) 21/29 (72%)

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chondrosarcomas.

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important role of CDK4 in chondrosarcoma progression.

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central chondrosarcoma, as found in the present and previous studies. Correlations are posi- tive, unless stated otherwise.



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in three chondrosarcoma cell lines.

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central chondrosarcomas.

Acknowledgements

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virus stocks. The authors thank I. Briaire-de Bruijn for technical assistance.

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Cancer Res 2009; 69:6216-22