title: Clinically relevant immunosuppressants influence UVB-induced tumor size through effects on inflammation and angiogenesis.
abstract: Immunosuppressive therapies allow long-term patient and transplant survival, but are associated with increased development of UV-induced skin cancers, particularly squamous cell carcinomas. The mechanisms by which CsA, MMF, tacrolimus (TAC) or sirolimus (SRL), alone or in dual combinations, influence tumor development and progression are not completely understood. In the current study, chronically UV-exposed mice treated with SRL alone or in combination with CsA or TAC developed more tumors than mice treated with vehicle or other immunosuppressants, but the tumors were significantly smaller and less advanced. Mice treated with CsA or TAC developed significantly larger tumors than vehicle-treated mice, and a larger percentage in the CsA group were malignant. The addition of MMF to CsA, but not to TAC, significantly reduced tumor size. Immunosuppressant effects on UVB-induced inflammation and tumor angiogenesis may explain these findings. CsA enhanced both UVB-induced inflammation and tumor blood vessel density, while MMF reduced inflammation. Addition of MMF to CsA reduced tumor size and vascularity. SRL did not affect inflammation, but significantly reduced tumor vascularity. Thus the choice of immunosuppressants has important implications for tumor number, size and progression, likely due to the influence of immunosuppressants on UVB-induced inflammation and angiogenesis.
authors.affiliation: Department of Surgery, The Ohio State University, Columbus, OH, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Duncan
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wulff
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Tober
authors.forename: Amy K
authors.initials: AK
authors.lastname: Ferketich
authors.forename: Jason
authors.initials: J
authors.lastname: Martin
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thomas-Ahner
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Allen
authors.forename: Donna F
authors.initials: DF
authors.lastname: Kusewitt
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Oberyszyn
authors.forename: Anne M
authors.initials: AM
authors.lastname: Vanbuskirk
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus