Spontaneous apoptosis of Reed-Sternberg and Hodgkin cells; clinical and pathological implications in patients with Hodgkin's disease.
The experiments were designed to study correlation between frequency of apoptosis of Reed-Sternberg/Hodgkin (R-S/H) cells, EBV infection of these cells, expression of the key proteins involved in regulation of apoptosis and cell cycle in R-S/H cells, the patients' pretreatment markers and the clinical outcome. One hundred and ten Hodgkin's disease (HD) patients were studies, of which 69 obtained complete remission (CR) after first-line treatment and 41 did not respond. The time of follow-up was from 18 to 242, median 69.7, months. Apoptosis was evaluated by TUNEL technique (TdT-mediated dUTP nick end labeling) and the presence of EBV-latent membrane protein 1 as well as expression of Bcl-2, tumor suppressor p53, p21WAF1, MDM-2, Rb1, PCNA, p27KIP1 and caspase-3, was detected immunocytochemically on paraffin-embedded lymph node specimens obtained at diagnosis. Positive TUNEL reaction was found in 43 patients with apoptotic index (AI) in this group varying between 10% and 60%. In the remaining 57 patients AI of R-S/H cells was below 10%. In 62 patients the cells surrounding R-S/H cells were also TUNEL-positive; their frequency was variable. The expression of LMP1 protein on R-S/H cells was found in 38 patients, without any correlation with the presence or frequency of apoptosis. No significant difference was seen between the AI and both clinical stage and histological type of the disease. However, the mean AI in non-responding patients was significantly higher than in CR group (p=0.015); the high frequency of apoptosis was also negatively correlated with the progression free survival time (p=0.031) and the overall survival (p=0.042). The expression of PCNA, p21WAF1, p53 protein and caspase-3 also showed positive correlation with frequency of apoptosis (p=0.011, p=0.036, and p=0.001, respectively). On the other hand, no statistically confirmed correlation was found between AI and expression of bcl-2, MDM-2, Rb1, and p27KIP1 on R-S/H cells. These data provide evidence that tumor cells in HD undergo spontaneous apoptosis regardless of EBV infection. High pretreatment AI correlates with poor response to the treatment, and may be considered as a potential negative prognostic factor in HD.
Brander Cancer Research Institute, New York Medical College, Hawthorne, NY 10532, USA. piotr_smolewski@nymc.edu
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D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D015415:Biomarkers; D014408:Biomarkers, Tumor; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections / Q000473:pathology; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006689:Hodgkin Disease / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000821:virology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2; D016539:Reed-Sternberg Cells / Q000473:pathology* / Q000821:virology; D012074:Remission Induction; D016160:Retinoblastoma Protein / Q000032:analysis; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins; D014412:Tumor Virus Infections / Q000473:pathology; D014763:Viral Matrix Proteins / Q000032:analysis
D015415:Biomarkers; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases