Tropism of herpes simplex virus type 1 to nonmelanoma skin cancers

Abstract

Current treatments for nonmelanoma skin cancer include surgery, Mohs micrographic surgery, radiation, cryosurgery, photodynamic therapy, local chemotherapy and application of immunomodulators such as imiquimod. However, all have a 5-year recurrence rate of 1-40%. Gene therapy for the treatment of skin cancers is a promising new approach, as delivery of the vectors to the skin is simple and safety issues can be properly addressed. To develop an ex-vivo organ culture system for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) tumours, and to test the feasibility of applying oncolytic viruses to these tumours. We first optimized conditions for the maintenance of BCC and SCC tissues in organ culture, and demonstrated viability of the tissues ex vivo for 3-7 days. The tropism of two potential oncolytic viral vectors, herpes simplex virus type 1 (HSV-1) and adenovirus (AD), was next evaluated. Immunohistological analysis revealed that HSV-1 targeted tumour cells that expressed p63 and did not express keratin 15 or keratin 14 markers of keratinocytes. Further examination indicated that uninfected BCC and SCC tissues express two isoforms of p63 mRNA, and HSV-1 infection specifically enhanced expression of the TAp63 isoform. Furthermore, following infection, both HSV-1 and AD induced apoptosis in the BCC and SCC cells as indicated by the induction of activated caspase-3. The results indicated a specific pattern of viral tropism to skin cancer cells that are critical for maintenance of the tumour. This new experimental system should aid in the analysis of new therapeutic modalities, such as oncolytic viruses, for future treatment of these skin tumours.