Chromosomal aberrations in UVB-induced tumors of immunosuppressed mice.
In immunocompromised individuals, such as organ transplant recipients, the risk of cutaneous squamous cell carcinoma (SCC) is increased 60-250 fold, and there is an increased likelihood to develop aggressive, metastatic SCC. An understanding of the genes involved in SCC tumorigenesis is critical to prevent SCC-associated morbidity and mortality. Mouse models show that different immunosuppressive drugs lead to SCCs varying in size, number, and malignant potential. In this study, we used mouse models that mimic adult transplant recipients to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporin (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridization. Mouse SCCs appear to show similar genomic aberrations as those reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial effects of drugs. Fewer aberrations were seen in tumors of mice treated with MMF or Rap. Tumors from Tac-treated animals showed the highest number of changes. Calcineurin inhibitors (Tac and CsA) did not cluster together by their genomic aberrations, indicating their contribution to UV mediated carcinogenesis may be through different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. Future studies will identify specific genes mapping to regions of aberration that are different between treatment groups to identify target pathways that may be affected by these drugs.
Dworkin
Amy M
AM
Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
Tober
Kathleen L
KL
Duncan
F Jason
FJ
Yu
Lianbo
L
VanBuskirk
Anne M
AM
Oberyszyn
Tatiana M
TM
Toland
Amanda Ewart
AE
D000704:Analysis of Variance; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000633:toxicity*; D051379:Mice; D008812:Mice, Hairless; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins