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Molecular Oncology, Markers, Clinical Correlates |
Department of Pathology/Laboratory for Experimental Patho-Oncology, Erasmus Medical Center/Daniel, Josephine Nefkens Institute, 3000 DR Rotterdam, the Netherlands [F. M., H. S., J. W. O., L. H. J. L.]; Department of Pathology, Free University Medical Center, 1081 HV Amsterdam, the Netherlands [G. L. S., R. S.]; and Department of Oncology, Hematology, Immunology, and Rheumatology, University of Tübingen Medical Center, 72076 Tübingen, Germany [F. M., C. B.]
Purpose: Germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy. This feature is unexplained, as is the intrinsic chemotherapy resistance of mature teratomas and the resistant phenotype of a minority of refractory GCTs. Various cellular pathways may influence the efficacy of chemotherapy. Their impact has not been investigated in a comprehensive study of tumor samples from clinically defined subgroups of GCT patients.
Experimental Design: We investigated proteins involved in regulation of apoptosis (p53, BAX, BCL-2, and BCL-XL), cell cycle control [p21 and retinoblastoma protein (RB)], and drug export and inactivation [P-glycoprotein, multidrug resistance-associated protein (MRP) 1, MRP2, breast cancer resistance protein, lung resistance protein, metallothionein, and glutathione S-transferase
] immunohistochemically in samples of unselected GCT patients (n = 20), patients with advanced metastatic disease in continuous remission after first-line chemotherapy (n = 12), and chemotherapy-refractory patients (n = 24). Mature teratoma components (n = 10) within tumor samples from all groups were analyzed separately. The apoptotic index was studied by terminal deoxynucleotidyl transferase-mediated nick end labeling assay.
Results: Invasive GCTs of all groups showed a correlation between wild-type p53 and apoptotic index (rs = 0.66; P < 0.001). The levels of the antiapoptotic proteins BCL-2 and BCL-XL were generally low. p21 was hardly detectable and did not correlate with p53 (rs = 0.29; P = 0.07). No significant differences among the three patient groups were identified regarding any of the investigated parameters (all Ps were >0.08), even though only individual samples from chemotherapy-resistant cases showed a strong staining for MRP2 and GST
. In contrast to other components, mature teratomas showed an intense p21 and RB staining and were mostly positive for MRP2, lung resistance protein, and GST
.
Conclusions: Our results indicate a multifactorial basis for the chemosensitivity of GCTs with lack of transporters for cisplatin, of antiapoptotic BCL-2 family members, of p21 induction by p53, and of RB and an intact apoptotic cascade downstream of p53. These findings suggest a preference for apoptosis over cell cycle arrest after up-regulation of p53. None of the examined parameters offers a general explanation for the chemotherapy-resistant phenotype of refractory tumors. The up-regulation of various factors interfering with chemotherapy efficacy and ability for a p21-induced cell cycle arrest may explain the intrinsic chemotherapy resistance of mature teratomas.
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