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Molecular Oncology, Markers, Clinical Correlates |
Departments of Medical Oncology [D. C. J. S., E. G. E. d. V., S. d. J.], Pathology [W. T.], Pulmonary Diseases [H. J. M. G.], and Biostatistics and Epidemiology [H. M. B.], University Hospital Groningen, Groningen 9713 GZ, the Netherlands
Purpose: Several in vitro studies have shown that non-small cell lung cancer (NSCLC) cell lines are sensitive to apoptosis induction by the recombinant human (rh) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death ligand, indicating that rhTRAIL might become an attractive molecule for treatment of NSCLCs. To investigate the therapeutic potential of rhTRAIL, the expression of TRAIL and its apoptosis-inducing receptors DR4 and DR5 was evaluated in tumors of stage III NSCLC patients.
Experimental Design: Before treatment, tumor biopsies from locally advanced NSCLC patients were obtained by bronchoscopy. DR4, DR5, and TRAIL expression were determined immunohistochemically in 87 tumors. Patients were randomized for treatment with 60 Gy radiotherapy with or without carboplatin as radiosensitizer.
Results: DR4, DR5, and TRAIL were expressed in 99%, 82%, and 91% of the tumors, respectively. Seventeen percent of the samples expressed only DR4 and no DR5. In NSCLCs with squamous cell differentiation, a typical staining pattern for DR4 and DR5 was observed. Cells from the basal layer were strongly positive, and the more mature cells were less positive or negative. An inverse staining pattern was observed for TRAIL. Poorly differentiated areas showed strong staining intensity for DR4, DR5, and TRAIL. DR5-positive staining was associated with increased risk of death (odds ratio, 5.76; 95% confidence interval, 1.04–31.93; P = 0.045).
Conclusions: The majority of the locally irresectable stage III NSCLCs expressed at least one of the two death receptors for TRAIL. Therefore, these death receptors may provide a target for the use of rhTRAIL as a new adjunct in the treatment of stage III NSCLC.
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