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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-04-1128.
Submitted April 12, 2002
Accepted August 21, 2002
Hodgkin's and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue-microarrays
Juan F Garcia*, Francisca I Camacho, Manuel Morente, Maximo Fraga, Carlos Montalban, Tomas Alavaro, Carmen Bellas, Angel Castano, Ana Diez, Teresa Flores, Carmen Martin, Miguel A Martinez, Francisco Mazorra, Javier Menarguez, Maria J Mestre, Manuela Mollejo, Ana I Saez, Lydia Sanchez, and Miguel A Piris
Programa de Patolgia Molecular, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain
Dep. A. Patologica, HC Universitario, Santiago de Compostela, Spain
S Med Interna, H Ramon y Cajal, Madrid, Spain
Dep. A. Patologica, H Verge de la Cinta, Tortosa, Spain
Dep. A. Patologica, H Ramon y Cajal, Madrid, Spain
Dep. A. Patologica, H Severo Ochoa, Leganes, Spain
Immunohistochemistry and Histology Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain
Dep. A. Patologica, H Clinico, Salamanca, Spain
Dep. A. Patologica, HUC San Carlos, Madrid, Spain
Dep. A. Patologica, HU 12 Octubre, Madrid, Spain
Dep. A. Patologica, H Marques de Valdecilla, Santander, Spain
Dep. A. Patologica, H Gregorio Maranon, Madrid, Spain
Dep. A. Patologica, H Mostoles, Madrid, Spain
Dep. A. Patologica, H Virgen de la Salud, Toledo, Spain
* Corresponding author; email: jfgarcia{at}cnio.es.
Tumoral cells in Hodgkin's Lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue Microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and ISH in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections.
The results revealed multiple alterations in different pathways and checkpoints, including G1/S, G2/M transition and apoptosis. Striking findings were the overexpression of Cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-XL, Survivin, and NF-kappaB proteins.
A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, Cyclins A, B1, D3, E, CDK2, CDK6, SKP2, Bcl-XL, Survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that EBV+ cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL.
Survival probability depends on multiple biological factors, including overexpression of Bcl2, p53, Bax, Bcl-XL, MIB1 and apoptotic index.
In conclusion, H/RS cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.
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