The cutaneous tumors derived by exposure to ultraviolet light (UV) are antigenic, and normally rejected when transplanted in syngeneic, immune competent recipients. The tumors escape immunological rejection in the original hosts because of a UV-mediated modulation of the immune system. Topical exposure to the tumor promoter 12-0-tetradecanoylphorbol-13- acetate (TPA) evokes an immunomodulation in SSIN (inbred SENCAR) mice that is similar to that caused by UV, which may be germane to the mechanism whereby TPA facilitates the development of initiated cells into tumors. Specifically, we have recently found that the primary papillomas generated in SSIN mice as a consequence of 7, 12-dimethylbenz[a] anthracene (DMBA) initiation / TPA promotion grow when s.c. transplanted into athymic nude mice, but regress and disappear when transplanted into naive, immune competent syngeneic or allogeneic hosts. Based upon these observations, we hypothesize that the papillomas generated in DMBA initiation / TPA-promotion protocols are antigenic, but escape rejection due to a promoter-mediated modulation of the immune system. In order to examine this hypothesis we propose: 1) to generate cell lines from skin papillomas harvested from initiated / TPA-promoted SSIN mice; 2) evaluate the in vivo growth / rejection of these cell lines and primary papillomas when s.c. transplanted into athymic nude mice, immunosuppressed syngeneic mice, and immune competent syngeneic mice; 3) determine if treatment of naive mice with initiating doses of DMBA, and / or promoting doses of TPA and other chemical promoters can suppress the rejection of s.c. transplanted papilloma cell lines or primary tumors; and 4) determine by adoptive transfer studies if the lack of immune rejection in initiated / promoted mice is mediated by an immune suppressor population. If so, the phenotype of the suppressor population will be characterized. 5) We will also determine the effects of topically applied TPA on antigen presentation and the activation and / or induction of anergy in CD4+ helper T cell subsets (e.g., Th1 and Th2 T cells), and 6) characterize the effects of DMBA and chemical promoters on the effector cells (natural killer cells, cytotoxic T cells) that participate in tumor rejection. 7) In order to better approximate the environment of epidermal tumor growth, we will use epidermal chambers to assess the effects of in vivo topical promoter treatment on the growth/rejection of grafted papilloma cell lines in the epidermis. The proposed research addresses a topic that has been ignored by investigators in the tumor promotion field, and explores a new and unique mechanism that might be germane to the mechanism whereby chemical promoters facilitate the development of initiated cells into tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049935-08
Application #
2007770
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Okano, Paul
Project Start
1989-09-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1998-11-30
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Organized Research Units
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
McCabe Jr, M J; Singh, K P; Reiners Jr, J J (2001) Low level lead exposure in vitro stimulates the proliferation and expansion of alloantigen-reactive CD4(high) T cells. Toxicol Appl Pharmacol 177:219-31
McCabe Jr, M J; Singh, K P; Reiners Jr, J J (1999) Lead intoxication impairs the generation of a delayed type hypersensitivity response. Toxicology 139:255-64
Reiners Jr, J J; Singh, K P; Yoon, H L et al. (1997) Transplantation analyses of the immunogenicity of epidermal tumors generated in murine skin two-stage carcinogenesis protocols. Mol Carcinog 20:48-57
Reiners Jr, J J; Singh, K P (1997) Susceptibility of 129/SvEv mice in two-stage carcinogenesis protocols to 12-O-tetradecanoylphorbol-13-acetate promotion. Carcinogenesis 18:593-7
Yoon, H L; Singh, K P; Ratner, S et al. (1996) Phorbol ester effects on splenic lymphocyte composition and cytotoxic T cell activities of SSIN mice: a strain deficient in CD8+ T cells. Carcinogenesis 17:2617-24
Singh, K P; Yoon, H L; Ratner, S et al. (1996) Modulation of the development of humoral immunity by topically applied acetone, ethanol, and 12-O-tetradecanoylphorbol-13-acetate. Fundam Appl Toxicol 33:129-39
Reiners Jr, J J; Pavone, A; Maldve, R et al. (1993) 12-O-tetradecanoylphorbol-13-acetate-mediated systemic co-promotion in the murine skin multistage carcinogenesis protocol. Carcinogenesis 14:411-5
Kodari, E; Pavone, A; Reiners Jr, J J (1993) Differential modulation of contact hypersensitivity and delayed hypersensitivity reactions by topical application of 12-O-tetradecanoylphorbol-13-acetate. Immunopharmacol Immunotoxicol 15:639-47
Reiners Jr, J J; Cantu, A; Thai, G et al. (1993) Differential co-promoting activities of alpha, beta and gamma interferons in the murine skin two-stage carcinogenesis model. Carcinogenesis 14:367-72
Gimenez-Conti, I B; Bianchi, A B; Fischer, S M et al. (1992) Dissociation of sensitivities to tumor promotion and progression in outbred and inbred SENCAR mice. Cancer Res 52:3432-5

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