[Antiangiogenic and anti-immunosuppressive therapeutic strategies in human head and neck squamous cell carcinoma (HNSCC)].
BACKGROUND
Angiogenesis and tumor-associated immunosuppression are two of the hallmarks of carcinogenesis. In previous studies we demonstrated in vitro that HNSCC tumor cells attract monocytes via monocyte chemotactic protein-1 (MCP-1) and activate them via transforming growth factor-beta 1(TGF-beta1) to secrete interleukin (IL)-1alpha, which in turn stimulates tumor cells to secrete increased levels of the angiogenic and immunosuppressive vascular endothelial growth factor (VEGF). These findings suggest that interaction between the immune system and VEGF-mediated angiogenesis is important for progression of HNSCC. Recent studies in vitro show that retinoic acid (RA) downregulates the release of MCP-1 and TGF-beta1 by tumor cells. Therefore, we investigated the ability of RA to modulate the ability of tumor cells to recruit and activate monocytes for participation in VEGF-mediated angiogenesis and immunosuppression in vivo.


METHODS
Mice (ten/group) were injected daily with RA (160 microg/kg) for 3 weeks. After that time mice were sacrificed, and paraffin sections of tumors were obtained and stained for VEGF-A, CD68, and PECAM (CD31) by immunohistochemistry. The lungs, liver, and myocardium were analyzed for macro- and micrometastases. The plasma protein levels of VEGF-A and MCP-1 were determined by ELISA.


RESULTS
In RA-treated mice tumors regressed completely and RA prevented metastases (p=0.00) and macrophage infiltration (p=0.007). Treated mice downregulated VEGF-A (0 pg/ml) and MCP-1 (12 pg/ml) in peripheral blood (p=0.001).


CONCLUSIONS
Our findings suggest a new therapeutic possibility: the development of treatment protocols that can block each of the ways in which tumors induce new blood vessel growth and immunosuppression of the host.
Strauss
L
L
Abteilung Onkologie, Universitätsspital Zürich. strauss_ewers@hotmail.com
Volland
D
D
Guerrero
A
A
Reichert
T
T
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000276:immunology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000502:physiology; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007375:Interleukin-1 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009062:Mouth Neoplasms / Q000098:blood supply* / Q000276:immunology*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D020533:Angiogenesis Inhibitors; D018932:Chemokine CCL2; D007375:Interleukin-1; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D014212:Tretinoin