publications, Personnel

Research Interests

The role of ultraviolet radiation in skin cancer is the focus of our research program. Our area of expertise is photoimmunology and photobiology, in particular the immunologic consequences of exposure to ultraviolet B (UVB, 290-320nm) radiation and their role in skin cancer outgrowth. The current aims of our laboratory are a) to identify the active wavebands of UV involved in melanoma induction using a unique mouse model for melanoma we have derived (Nature, 413:271-2, 2001), b) to investigate the role of UV effects on immunity in melanoma induction and c) to identify the genes controlling susceptibility to UV-induced immunosuppression and to establish how these contribute to skin cancer development.

Photoimmunology: A relationship between sunlight exposure and human skin cancer is well established. The incidence of all types of skin cancer is increasing worldwide and malignant melanoma, the most lethal of skin cancers, is one of the fastest increasing cancers in the USA. It is therefore critical to understand the mechanisms and to identify risk factors for these diseases. A body of experimental evidence has resulted in a model for skin cancer formation in which UVB initiates two separate events, the neoplastic transformation of skin cells and a well-described selective down-regulation of immune function. UVB initiates a dose and wavelength dependent down regulation or suppression of cell-mediated immunity observed both in experimental animals and in humans. There is considerable evidence from experimental systems that this form of immunosuppression is a critical step in UV carcinogenesis, preventing immunologic destruction of highly antigenic UV-induced skin cancers. UVB-induced immune suppression appears to be a fundamental regulatory mechanism, controlling interaction between mammals and potentially deleterious environmental radiation. This mechanism may have evolved to protect against autoimmune attack on sunlight altered skin. An inadvertent consequence of this protective mechanism, however, appears to be the prevention of immune attack on UV-induced skin cancers.

Our research has contributed significantly to an understanding of the mechanisms of UV radiation-induced alterations to the immune system and their role in skin cancer. Our initial studies were fundamental in establishing the photobiologic and immunologic characteristics of UV-induced immunosuppression. We identified the wavebands of UV responsible (UVB, 280-320nm) and their dose-response characteristics. We carried out a narrow band action spectrum or wavelength dependence study for UV-induced immunosuppression and identified a skin photoreceptor, urocanic acid, which undergoes a trans to cis isomerization in response to UV radiation as an initiator of this effect. This finding has since been substantially confirmed and extended in more than 250 papers in the literature.

We established, in collaborative studies, that a systemic alteration to the function of antigen-presenting cells, postulated to direct the formation of down regulatory T cells, is central to the mechanism of UV immunosuppression. We were then able to demonstrate that cis-UCA administered in vivo could cause a functional defect in the highly potent antigen presenting cells, splenic dendritic cells, similar to that caused by UV irradiation. This study provided further evidence for the mechanism of action of cis-UCA and for the central role of antigen presenting cell alterations in UV immunosuppression. These findings were later confirmed in the literature.

UV induction of melanoma: Using a transgenic mouse model, in collaboration with the laboratory of Dr Glenn Merlino, National Cancer Institute, we have recently derived a new mouse model for UV-induced melanoma which shows strong similarities to human melanoma in etiology, in histopathology and molecular pathogenesis. A high incidence of junctional melanoma was observed in HGF/SF transgenic mice which had been neonatally exposed to UV radiation. In contrast, adult UV irradiation of the same animals initiated only non-melanoma skin cancers. These findings provide an experimental basis for the epidemiologic observations that childhood sunlight exposure is critical for subsequent melanoma formation.

Genetics: Most recently, we have investigated the genetics of susceptibility to UV-induced immunosuppression using inbred strains of mice. Because of the role of UV-induced immunosuppression in UV carcinogenesis, it has been postulated that genetically determined susceptibility to UV-induced immunosuppression is an independent risk factor for skin cancer. We established that susceptibility to UV-induced immunosuppression is controlled by interacting autosomal and X-linked genes.

In a collaborative study, an essential role of dermal mast cells in UV immunosuppression was demonstrated, enabling us to postulate that at least some of the genes controlling susceptibility to UV-induced immunosuppression are mast cell related.

Finally, we have carried out a genetic linkage study as a first step in identification of the autosomal genes. Using novel methodologies of analysis, we have identified 3 quantitative trait loci (QTLs) for this effect and a further 3 QTLs which appear to show a three-way interaction. These are the first QTLs for this effect and, as far as we can establish, the first QTLs for any UV related response. We believe that, in the long term, these studies will lead to identification of genes controlling susceptibility to UV immunosuppression and thus susceptibility to skin cancer in man.

Selected Publications Top

· F. P. Noonan, J. A. Recio, H. Takayama, P. Duray, M. R. Anver, W. L. Rush, G. Lindner, E. C. De Fabo, and G. Merlino. Neonatal sunburn and melanoma in mice. Nature, 413:271-2, 2001.

· F.P. Noonan, T. Otsuka S.Bang, M.Anver and G.Merlino (2000). Accelerated UV carcinogenesis in hepatocyte growth factor/ scatter factor transgenic mice Cancer Res. 60: 3738-3743

· E. C. De Fabo and Noonan, F.P. Ultraviolet-B radiation and stratospheric ozone loss: potential impacts on human health in the arctic. Int J Circumpolar Health 2000. 59(1):4.-8

· E. C. De Fabo Stratospheric ozone depletion: UVB "Effects", the neglected aspect [editorial] Int J Circumpolar Health 2000. 59(1): 2.-3.

· K.E. Clemens, N. Bhatt, K. R. Richardson, G. A. Churchill and F. P. Noonan, (2000) Genetic control of susceptibility to UV-induced immunosuppression by interacting quantitative trait loci. Genes and Immunity, 1:251-259.

· Hart , P.H., Grimbaldeston, M.A., Swift, G.J., Noonan, F.P. and Finlay-Jones, J.J. (1998) Dermal mast cells determine susceptibility to UVB-induced suppression of contact hypersensitivity responses in mice. J. Exp. Med. 187: 2045-2053.

· B. Bouscarel, Noonan, F.P., Ceryak, S., Gettys, T.W., Phillips, T.M., and E.C De Fabo. Regulation of stimulated cyclic AMP synthesis by urocanic acid. Photochem. Photobiol.. 1998. 67(3): 324-331.

· S.A.J. IJland, F. P. Noonan , S. Ceryak, D.P.T. Steenvoorden, B. Bouscarel, D.Hug, G. M.J. Beijersbergen van Henegouwen and E. De Fabo (1998) Urocanic acid does not photobind to DNA in mice irradiated with immunosuppressive doses of UVB. Photochem. Photobiol. 67 : 222-226

· Noonan, F.P. and Hoffman, H.A. (1994) Control of UVB immunosuppression in the mouse by autosomal and sex-linked factors. Immunogenetics 40: 247-256.

· Noonan, F.P. and De Fabo, E.C. (1992). Immunosuppression by ultraviolet B radiation: initiation by urocanic acid. Immunology Today. 13: 250-254.

· De Fabo, E.C. and Noonan, F.P. (1983). Mechanism of immune suppression by UV irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology. J. Exp. Med. 157:84-98.

Personnel Top

Heather Poetschke-Klug, PhD. Post-doctoral Fellow, National Institutes of Health (collaboration with Dr G. Merlino, Molecular Genetics Section, Laboratory of Molecular Biology, National Cancer Institute).

James Dudek, MS. Graduate Student, Genetics Program, The George Washington Institute for Biomedical Sciences.

Kirstie Carter. Research Assistant.