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.
Aebersold
D M
DM
Department of Radiation Oncology, Inselspital, University of Bern, Bern, Switzerland.
Kollar
A
A
Beer
K T
KT
Laissue
J
J
Greiner
R H
RH
Djonov
V
V
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