title: Sirolimus reduces the incidence and progression of UVB-induced skin cancer in SKH mice even with co-administration of cyclosporine A.
abstract: Transplant immunosuppressants have been implicated in the increased incidence of non-melanoma skin cancer in transplant recipients, most of whom harbor considerable UVB-induced DNA damage in their skin prior to transplantation. This study was designed to evaluate the effects of two commonly used immunosuppressive drugs, cyclosporine A (CsA) and sirolimus (SRL), on the development and progression of UVB-induced non-melanoma skin cancer. SKH-1 hairless mice were exposed to UVB alone for 15 weeks, and then were treated with CsA, SRL, or CsA+SRL for 9 weeks following cessation of UVB treatment. Compared with vehicle, CsA treatment resulted in enhanced tumor size and progression. In contrast, mice treated with SRL or CsA+SRL had decreased tumor multiplicity, size, and progression compared with vehicle-treated mice. CsA, but not SRL or combined treatment, increased dermal mast cell numbers and TGF-beta1 levels in the skin. These findings demonstrate that specific immunosuppressive agents differentially alter the cutaneous tumor microenvironment, which in turn may contribute to enhanced development of UVB-induced skin cancer in transplant recipients. Furthermore, these results suggest that CsA alone causes enhanced growth and progression of skin cancer, whereas co-administration of SRL with CsA causes the opposite effect. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wulff
authors.forename: Donna F
authors.initials: DF
authors.lastname: Kusewitt
authors.forename: Anne M
authors.initials: AM
authors.lastname: VanBuskirk
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thomas-Ahner
authors.forename: F Jason
authors.initials: FJ
authors.lastname: Duncan
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Oberyszyn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002452:Cell Count; D016572:Cyclosporine / Q000494:pharmacology*; D018450:Disease Progression; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015994:Incidence; D008198:Lymph Nodes / Q000473:pathology; D008407:Mast Cells / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D009381:Neoplasms, Radiation-Induced / Q000473:pathology / Q000517:prevention & control; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D009504:Neutrophils / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D020123:Sirolimus