Expression of TRAIL and TRAIL death receptors in stage III non-small cell lung cancer tumors.
OBJECTIVE
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.


METHODS
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.
Spierings
Diana C J
DC
Departments of Medical Oncology, University Hospital Groningen, Groningen 9713 GZ, the Netherlands.
de Vries
Elisabeth G E
EG
Timens
Wim
W
Groen
Harry J M
HJ
Boezen
H Marike
HM
de Jong
Steven
S
D051017:Apoptosis Regulatory Proteins; D001706:Biopsy; D015153:Blotting, Western; D016190:Carboplatin / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D016017:Odds Ratio; D011379:Prognosis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D011897:Random Allocation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D016190:Carboplatin