Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation.
The activation of cytoplasmic signal transduction pathways by a number of growth factors and their tyrosine-kinase receptors, including hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met, exerts an inhibitory influence on apoptosis induced by ionizing radiation in vitro. The clinical relevance of the aforementioned ligand-receptor pair, of Bcl-xL, which is targeted by HGF/SF/c-met signaling, and of Bcl-2, was assessed by evaluating their predictive and prognostic impact in a cohort of 97 patients with radically irradiated squamous cell cancers of the oropharynx. Immunohistochemical expression of c-met and Bcl-xL was correlated with decreased rates of complete remission of the primary tumor in both the univariate (c-met: P = 0.01; Bcl-xL: P = 0.001) and multivariate analyses. Expression of c-met was, moreover, a significant and independent predictor of impaired local failure-free survival (P = 0.003), disease-free survival (P = 0.003) and overall survival (p = 0.001). Bcl-2 expression was, on the other hand, associated with a favorable outcome, in terms of both local failure-free survival (P = 0.01) and overall survival (P = 0.001). In accordance with in vitro data, c-met and Bcl-xL appear to be involved in the resistance of oropharyngeal cancers to ionizing radiation, and may therefore represent attractive targets for radiosensitization.
Department of Radiation Oncology, Inselspital, University of Bern, Bern, Switzerland.
D M
DM
Aebersold
A
A
Kollar
K T
KT
Beer
J
J
Laissue
R H
RH
Greiner
V
V
Djonov
D000368:Aged; D017209:Apoptosis / Q000528:radiation effects; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009959:Oropharyngeal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000502:physiology*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012074:Remission Induction; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met