Retinoic acid modulates the ability of macrophages to participate in the induction of the angiogenic phenotype in head and neck squamous cell carcinoma.
Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of angiogenesis and are of prognostic value in some neoplasms. Specimens from head and neck squamous cell carcinomas (HNSCC) often contain large numbers of TAMs. In addition, experimental evidence has demonstrated that HNSCC tumor cells can attract and activate macrophages to participate in the expression of the angiogenic phenotype. These findings suggest that antiangiogenic therapies for HNSCC must include strategies that will block the recruitment of macrophages into the tumor microenvironment. We investigated the ability of retinoic acid (RA) to modulate the ability of tumor cells to recruit and activate monocytes for participation in tumor angiogenesis. Owing to a decrease in the secretion of MCP-1 and transforming growth factor-beta 1 (TGF-beta 1), tumor cells treated with RA were unable to induce peripheral blood monocyte (PBM) chemotaxis. Also, as a result of the decrease in TGF-beta 1 secretion, RA-treated tumor cells were unable to activate macrophages for secretion of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In addition to its affects on tumor cells, RA also directly altered the ability of monocytes to participate in the tumor angiogenesis process. PBM exposed to RA were unable to migrate toward inducers of PBM such as MCP-1 and TGF-beta 1. Finally, RA decreased the ability of tumor-activated macrophages to secrete IL-8 and VEGF. These data demonstrate alternative mechanisms by which RA may modulate angiogenesis in the tumor microenvironment. In addition, it underscores the necessity to develop antiangiogenic treatment protocols that can block each of the ways in which new blood vessel growth is induced in tumor microenvironments.
Liss
Cory
C
Department of Pathology, The Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, USA.
Fekete
Mary Jo
MJ
Hasina
Rifat
R
Lingen
Mark W
MW
D002294:Carcinoma, Squamous Cell / Q000098:blood supply*; D002465:Cell Movement; D016228:Endothelial Growth Factors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000098:blood supply*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010641:Phenotype; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014212:Tretinoin