Although there are circumstantial links between inflammation and squamous cell carcinoma growth, there have been no studies that have directly examined the critical role of activated leukocytes and pro-inflammatory cytokines to skin multistage carcinogenesis. The hypothesis for the proposed studies is that leukocytes and cytokines produced by leukocytes and epidermal keratinocytes are essential to the growth of skin papillomas induced in transgenic TG.AC mice that contain an activated v-Ha-ras by 5 topical treatments with 2 yg TPA or by exposure to 100 nmol 7,12 DMBA. The importance of leukocytes and pro-inflammatory cytokines to malignant conversion of papillomas to carcinomas will be assessed in Sencar mice treated with a single 20 yg dose of DMBA followed by 5 treatments with 2 yg TPA which induces papillomas with a high rate of malignant conversion. Selective inhibition of dermal leukocyte infiltration or inhibition of synthesis of pro-inflammatory cytokines will effectively inhibit (a) the formation of DNA lesions that are sensitive to formamido-N-glycosylase (FaPY), Endonuclease III and IV: (b) proliferation of keratinocyte subpopulations within the epidermis and follicular regions; (c) growth of papillomas and (d) the rate of conversion of papillomas to carcinomas. To examine this hypothesis, the following Specific Aims are proposed: 1) Examine the ability of the cytokine synthesis inhibitor Pentoxifylline to inhibit infiltration of leukocyte populations, inhibit cytokine gene expression, inhibit DNA damage and oxidative 8-oxo-dG adduct formation in TG.AC v-Ha-ras transgenic mice during papilloma growth induced by either 100 nmol DMBA or 2 yg TPA; 2) Examine the effect of i.v. injection of TG.AC v-Ha-ras transgenic mice with anti-B2 integrin antibodies on tumor promotion; 3) Determine the extent to which inflammation contributes to conversion of papillomas to carcinomas by examining the effect of administration of either Pentoxifylline or anti-B2 integrin antibodies on cyclin D1 overexpression and the timing of development of mutations within exons 5-8 of the p53 tumor suppressor gene which is mutated at high frequency during malignant conversion. These studies provide the unique opportunity to determine the direct link between inflammation, promotion and malignant conversion.
| Oberyszyn, T M; Conti, C J; Ross, M S et al. (1998) Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion. Carcinogenesis 19:445-55 |
