HSP90 as a marker of progression in melanoma

被引:96
作者
McCarthy, M. M. [1 ]
Pick, E. [1 ]
Kluger, Y. [4 ]
Gould-Rothberg, B. [2 ]
Lazova, R. [3 ]
Camp, R. L. [2 ]
Rimm, D. L. [2 ]
Kluger, H. M. [1 ]
机构
[1] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA
[2] NYU, Dept Cell Biol, New York, NY 10016 USA
[3] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA
[4] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA
关键词
chaperones; diagnostic markers; HSP90; progression markers; therapeutic targets;
D O I
10.1093/annonc/mdm545
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: HSP90 chaperones molecules critical for cell survival and malignant progression, including mutated B-raf. HSP90-targeting agents are in clinical trials. No large studies have been conducted on expression of HSP90 in melanomas. Materials and methods: Tissue microarrays containing 414 nevi, 198 primary and 270 metastatic melanomas were assessed using our automated quantitative analysis (AQUA) method of in situ protein measurement; we use S-100 to define pixels as melanocytes (tumor mask) within the array spot, and measure HSP90 expression within the mask using Cy5-conjugated antibodies. Results: HSP90 expression was higher in melanomas than nevi (P < 0.0001) and higher in metastatic than primary specimens (P < 0.0001). No association was seen between high HSP90 expression and survival in the primary or metastatic patient subsets. In primary melanomas, high HSP90 expression was associated with higher Clark level (P = 0.0167) and increased Breslow depth (P < 0.0001). Conclusions: HSP90 expression was significantly higher in tumors than nevi and was associated with disease progression, indicating that it might be a valuable drug target in melanoma, as well as a useful diagnostic marker. Prospective studies are needed to confirm the diagnostic role of HSP90, as well as the predictive role of HSP90 expression in patients treated with HSP90 inhibitors.
引用
收藏
页码:590 / 594
页数:5
相关论文
共 25 条
[1]   Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies [J].
Banerji, U ;
O'Donnell, A ;
Scurr, M ;
Pacey, S ;
Stapleton, S ;
Asad, Y ;
Simmons, L ;
Maloney, A ;
Raynaud, F ;
Campbell, M ;
Walton, M ;
Lakhani, S ;
Kaye, S ;
Workman, P ;
Judson, I .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (18) :4152-4161
[2]   Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases [J].
Becker, B ;
Multhoff, G ;
Farkas, B ;
Wild, PJ ;
Landthaler, M ;
Stolz, W ;
Vogt, T .
EXPERIMENTAL DERMATOLOGY, 2004, 13 (01) :27-32
[3]   Automated subcellular localization and quantification of protein expression in tissue microarrays [J].
Camp, RL ;
Chung, GG ;
Rimm, DL .
NATURE MEDICINE, 2002, 8 (11) :1323-1327
[4]   Hsp90 as a target for drug development [J].
Chaudhury, Subhabrata ;
Welch, Timothy R. ;
Blagg, Brian S. J. .
CHEMMEDCHEM, 2006, 1 (12) :1331-+
[5]  
Chiosis G, 2003, MOL CANCER THER, V2, P123
[6]   Mutations of the BRAF gene in human cancer [J].
Davies, H ;
Bignell, GR ;
Cox, C ;
Stephens, P ;
Edkins, S ;
Clegg, S ;
Teague, J ;
Woffendin, H ;
Garnett, MJ ;
Bottomley, W ;
Davis, N ;
Dicks, N ;
Ewing, R ;
Floyd, Y ;
Gray, K ;
Hall, S ;
Hawes, R ;
Hughes, J ;
Kosmidou, V ;
Menzies, A ;
Mould, C ;
Parker, A ;
Stevens, C ;
Watt, S ;
Hooper, S ;
Wilson, R ;
Jayatilake, H ;
Gusterson, BA ;
Cooper, C ;
Shipley, J ;
Hargrave, D ;
Pritchard-Jones, K ;
Maitland, N ;
Chenevix-Trench, G ;
Riggins, GJ ;
Bigner, DD ;
Palmieri, G ;
Cossu, A ;
Flanagan, A ;
Nicholson, A ;
Ho, JWC ;
Leung, SY ;
Yuen, ST ;
Weber, BL ;
Siegler, HF ;
Darrow, TL ;
Paterson, H ;
Marais, R ;
Marshall, CJ ;
Wooster, R .
NATURE, 2002, 417 (6892) :949-954
[7]   Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin [J].
Dias, SD ;
Friedlos, F ;
Light, Y ;
Springer, C ;
Workman, P ;
Marais, R .
CANCER RESEARCH, 2005, 65 (23) :10686-10691
[8]   Heat shock protein 70 membrane expression and melanoma-associated marker phenotype in primary and metastatic melanoma [J].
Farkas, B ;
Hantschel, M ;
Magyarlaki, M ;
Becker, B ;
Scherer, K ;
Landthaler, M ;
Pfister, K ;
Gehrmann, M ;
Gross, C ;
Mackensen, A ;
Multhoff, G .
MELANOMA RESEARCH, 2003, 13 (02) :147-152
[9]   UNUSUAL EXPRESSION AND LOCALIZATION OF HEAT-SHOCK PROTEINS IN HUMAN TUMOR-CELLS [J].
FERRARINI, M ;
HELTAI, S ;
ZOCCHI, MR ;
RUGARLI, C .
INTERNATIONAL JOURNAL OF CANCER, 1992, 51 (04) :613-619
[10]   V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors [J].
Grbovic, OM ;
Basso, AD ;
Sawai, A ;
Ye, Q ;
Friedlander, P ;
Solit, D ;
Rosen, N .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (01) :57-62