Conversion of Herpetic Lesions to Malignancy by Ultraviolet Exposure and Promoter Application

Abstract

SUMMARYMany lines of evidence exist associating herpes simplex virus (HSV) with the development of carcinoma, but much of this evidence is anecdotal or associative in nature and does not prove a cause and effect. The purpose of this research was to investigate the oncogenic potential of HSV type 2 (HSV-2) in vivo. A mouse model for lip carcinogenesis was designed to combine HSV-2 infection, u.v. exposure and tetradecanoyl-phorbol-acetate (TPA) application. HSV-2 inoculation on to abraded mouse lips was capable of causing vesicular ulcerative lesions which healed completely after 10 to 14 days. Ultraviolet irradiation of the HSV lesion site daily for 6 min at 42 ergs/mmVs on days 3 to 6 post-infection caused hyperkeratosis, acanthosis and dyslblasia to develop in several lips; while the same u.v. exposure by itself failed to alter the histologic appearance. The addition of repeated TPA application to the HSV+ u.v. regimen promoted tumour emergence. Thirty-two of 156 Balb/c mice developed tumours. Although the majority were papillomas, six were squamous cell carcinomas. These tumour-bearing mice had increased HSV-specific antibody titres. HSV antigens were shown to be present in outgrowths from explanted tumours as well as in tumour biopsies by immunoperoxidase staining with HSV-specific antisera. It is suggested that the in vivo u.v.-irradiated HSV acted as the inducer and TPA as the promoter, analogous to the classical two-stage carcinogenesis model.

Effects of Acycloviru on Herpes Simplex Virus Type 1 Infection in Mice Treated with 12-O-Tetradecanoylphorbol 13-acetate

“…On the other hand, with increased time of latency, irreversible and malignant lesions would have had a better chance to develop. The difference in tumour incidence between this study and the one by Burns & Murray (1981) might indicate that HSV-2 has a more potent initiating capacity than HSV-1. However, the different methods of inactivation of HSV after infection might well have been an important factor.…”

“…However, if the results for the animals that received HSV inocula and TPA, with or without acyclovir (groups I and II), are added together, the differences in incidence of lip tumours as well as of all tumours are statistically significant (P ~< 0-05) when compared with animals not receiving this combined treatment (groups III, IV and V). Burns & Murray (1981) used a classical model of initiator, cofactor and promoter to study the incidence of tumours in the treated area, i.e. the mouse lip.…”

“…It has clearly been established that inactivated HSV-1 is capable of transforming cells in vitro (Rapp, 1980) and circumstantial evidence supports the conclusion that HSV is associated with some human cancers (Shillitoe & Silverman, 1979). Burns & Murray (1981) reported that inoculation of HSV-2 on abraded mouse lips followed by u.v. irradiation and exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA) application resulted in the development of both squamous cell carcinomas and papillomas of the lip.…”

Construction of Rat Cell Lines that Contain Potential Morphologically Transforming Regions of the Herpes Simplex Virus Type 2 Genome

“…It has been demonstrated that treatment of recipient cells with chemical carcinogens or UV irradiation of in vivo infected areas signi ficantly enhances the transforming or onco genic potential of HSV [22,23]. This may indicate that HSV acts as a cofactor in the transformation process and does not need to be continuously present or expressed.…”

Studies on chemical carcinogen enhancement of epstein‐barr virus induced transformation of human neonatal and adult peripheral blood lymphocytes

“…The enhancing effects of chemical and physical carcinogens on animal cell transformation by oncogenic viruses have been well documented in adenovirus type 12, SV (simian virus) 40, polyoma and retrovirus systems. It has also been possible to demonstrate synergism between herpes simplex virus type 2 (HSV-2), UV irradiation, and tumor promotion in the development of malignancy (Burns and Murray, 1981). These results may well have been inferred from the in vitro experiments of Johnson (1982), demonstrating the ability of chemical carcinogens to enhance HSV-2induced 3T3 mouse cell transformation.…”