Dual role of VEGF family members in the pathogenesis of head and neck cancer (HNSCC): possible link between angiogenesis and immune tolerance.
BACKGROUND
Antigen presenting cells, in particular dendritic cells (DCs), are critical elements in antitumor immunity induction. Some of the angiogenic factors released by tumor and stroma cells, including vascular endothelial growth factor (VEGF), are thought to affect DC function.


METHODS
The expression of Vascular Endothelial Growth Factor (VEGF) isoforms VEGF-A (121, 145,165, 189, 206), VEGF-C and VEGF-D were determined by immunohistochemistry, Western blotting and ELISA in 46 patients with Head and Neck Squamous Cell Carcinoma (HNSCC), 30 healthy donors, and two HNSCC tumor cell lines (PCI-1 and PCI-13).


RESULTS
Increased expression of VEGF-A and VEGF-C was found in tumor tissues compared to normal epithelium (P=0.001). However, VEGF-D levels were decreased in patients with cervical nodal metastasis as compared to patients with negative lymph node status. VEGF-A plasma levels were increased in patients with lymph node metastasis (266 pg/ml) compared to patients with negative lymph node status (19.8 pg/ml). Multivariate analysis demonstrated that VEGF-A correlated with microvessel density (P=0.01), disease progression (P=0.038), a reduced number of local and peripheral mature dendritic cells (DC) (P=0.015) and an increased number of peripheral immature DCs (P=0.05). DCs incubated with tumor supernatant or VEGF-A differentiated into immature DCs and did not develop full allostimulatory activity. Allogenic T cells, when co-cultured with these immature DCs, expressed the T regulatory cell marker CD25, CTLA-4, and CD45Ro, and secreted TGF-beta, VEGF-A and IL-10.


CONCLUSIONS
Taken together, our results identify VEGF-A as a multifunctional factor involved in angiogenesis, tumor progression, immunosuppression and immune tolerance.
Strauss
Laura
L
Department of Oral and Maxillofacial Surgery, University Hospital Mainz, Mainz, Germany. strauss_ewers@hotmail.com
Volland
Dagmar
D
Kunkel
Martin
M
Reichert
Torsten Eugen
TE
D000328:Adult; D000368:Aged; D002452:Cell Count; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D042442:Vascular Endothelial Growth Factors / Q000097:blood / Q000145:classification / Q000378:metabolism*
D020033:Protein Isoforms; D042442:Vascular Endothelial Growth Factors