Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays.
Tumoral cells in Hodgkin 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 a 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 in situ hybridization 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 and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg 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.
García
Juan F
JF
Lymphoma Group, Molecular Pathology Program, and Immunohistochemistry and Histology Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. jfgarcia@cnio.es
Camacho
Francisca I
FI
Morente
Manuel
M
Fraga
Máximo
M
Montalbán
Carlos
C
Alvaro
Tomás
T
Bellas
Carmen
C
Castaño
Angel
A
Díez
Ana
A
Flores
Teresa
T
Martin
Carmen
C
Martinez
Miguel A
MA
Mazorra
Francisco
F
Menárguez
Javier
J
Mestre
Maria J
MJ
Mollejo
Manuela
M
Sáez
Ana I
AI
Sánchez
Lydia
L
Piris
Miguel A
MA
D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000032:analysis*; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis
D015415:Biomarkers; D018797:Cell Cycle Proteins