The platelet-derived growth factor receptor as a target for vascular endothelial growth factor-mediated anti-angiogenetic therapy in head and neck cancer.
Inhibition of angiogenesis by blocking angiogenic cytokines or their pathways has become a major target in experimental cancer therapies. This therapeutical approach requires a profound knowledge of growth factor profiles that contribute to tumor growth and progression. The respective knowledge is presently rather incomplete for head and neck squamous cell carcinomas (HNSCC). Therefore we studied the serum levels and expression of platelet-derived growth factor (PDGF) in HNSCC patients and in cell culture as well as the effect of a PDGF-receptor (PDGF-R) inhibition by Imatinib (Gleevec, STI571) on the secretion and expression activity of PDGF and vascular endothelial growth factor (VEGF) by postulating there is a correlation between the PDGF and VEGF networks. PDGF levels in patients with HNSCC, PDGF and VEGF secretion by HNSCC cells, were measured by ELISA, expression of PDGF and VEGF by RT-PCR. We found significantly increased PDGF levels in HNSCC patients' sera as well as in HNSCC cell lines. Treatment of the cell lines with Imatinib, a partially selective PDGF-R inhibitor, resulted in reduced secretion of PDGF and VEGF. This inhibiting effect was also reflected on the expression level of VEGF. In conclusion, the present study confirms the crucial role of PDGF in HNSCC growth and strongly suggests a correlation between the PDGF/PDGF-R and VEGF/VEGF-R pathway networks in HNSCC. Although further studies must be performed for a more complete understanding of this interaction, a targeting therapy for the inhibition of PDGF-R tyrosine phosphorylation by Imatinib may be a promising strategy for future tumor therapy by autocrine and paracrine inhibition of tumor growth and angiogenesis, presumably through simultaneous down-regulation of PDGF and VEGF.
Bran
Birgit
B
University HNO-Klinik, Klinikum Theodor-Kutzer-Ufer, D-68135 Mannheim, Germany. birgit.bran@gmx.de
Bran
Gregor
G
Hörmann
Karl
K
Riedel
Frank
F
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor