Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis.
BACKGROUND
The expression of vascular endothelial growth factor (VEGF)-A isoforms (121, 165, 189, 206), VEGF-B, VEGF-C and VEGF-D in both experimental and clinical models of head and neck squamous cell carcinoma (HNSCC) was determined and correlated with conventional clinicopathologic parameters, with particular reference to cervical nodal metastasis.


METHODS
The mRNA expression of VEGFs in 14 HNSCC cell lines was compared with 4 normal keratinocyte cultures and 10 fibroblast cultures using a semiquantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Protein levels were determined by Western blotting and enzyme-linked immunosorbent assay (ELISA). The authors then examined the expression of VEGFs in tissues from 54 patients including histologically normal epithelium (n = 32), early invasive squamous cell carcinomas (SCCs) (n = 23), advanced primary SCCs (n = 31), and lymph node metastases (n = 27).


RESULTS
Increased levels of VEGF-A (all four isoforms) and VEGF-C were found in tumor cell lines compared with normal cells, whereas no differences in VEGF-B levels were found. VEGF-D expression, however, was lower in HNSCC cells. Studies in clinical samples showed highly significant increases in mRNA expression of all four isoforms of VEGF-A and VEGF-C in tumors versus normal epithelium. In contrast, the levels of VEGF-D were significantly decreased in tumors, and VEGF-B expression appeared similar in both normal and malignant tissues. Multivariate analysis demonstrated that an infiltrative mode of invasion and enhanced expression of VEGF-A (isoforms 121 and 165) and VEGF-C had predictive value for the presence of cervical nodal metastases.


CONCLUSIONS
Up-regulation of VEGF-A (two isoforms) and VEGF-C and down-regulation of VEGF-D have been common features in HNSCC. Thus VEGF-A and VEGF-C appeared to play a vital role in the metastatic process of HNSCC.
O-charoenrat
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P
Department of Head and Neck Surgery, Royal Marsden Hospital, London, SW3 6JJ, United Kingdom. pornchaio@yahoo.co.uk
Rhys-Evans
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P
Eccles
S A
SA
D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000556:secondary*; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016015:Logistic Models; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000556:secondary; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D
D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D