Malignant melanoma is the most aggressive type of skin cancer. Although it is relatively rare, with a worldwide yearly incidence of about 160,000 cases, it is increasing in prevalence particularly among Caucasians living in regions where sunlight is intense.

It arises in melanocytes, which produce the pigment melanin. Exposure to the ultraviolet rays of the sun has been recognised for some time as the major risk factor for this cancer, but the mechanism through which ultraviolet light leads to carcinogenesis is still largely unknown.

A group of researchers based at the National Cancer Institute, Maryland, USA, working with collaborators in George Washington University, Washington DC and Rockefeller University, New York, have now used a mouse model both to validate the clear but largely epidemiological evidence of a link between ultraviolet light and melanoma on a molecular basis, and to further probe the mechanism of carcinogenesis.

Transgenic iDCT-GFP mice develop tumours that are similar to human melanomas only if exposed to ultraviolet-B (UVB) radiation as neonates. Melanocyte-containing skin samples were taken from iDCT-GFP mouse pups one and six days after exposure to either UVB or UVA radiation, and melanocyte gene expression profiles determined using microarrays. The stress response observed after UVB radiation was much more marked than that following UVA radiation, showing in particular increased expression of genes characteristically associated with interferon (IFN) response six days after UVB exposure.

The researchers then explored the involvement of interferon in melanocyte activation further by blocking the IFN-ab and IFN-g responses separately in UVB-exposed neonatal mice. Blockage of IFN-g but not IFN-ab was found to significantly inhibit the response, indicating that activation is mediated through IFN-g.

Interferons are released by lymphocytes as part of the immune response; their function is to aid cell-cell communication and thus immune defence. In order to determine the source of IFN-g in the irradiated melanocytes, the researchers examined the mouse skin using immunohistochemistry.

The only immune cells detected were macrophages; these were found to secrete IFN-g, supporting the theory that this is induces the characteristic pattern of gene expression seen in the melanocytes. Further investigation found the chemokine receptors Ccr2 and Ccr5 to be very strongly expressed in these macrophages.

Infiltration of the UVB-irradiated melanocytes by IFN-g expressing macrophages was found to coincide with a strong upregulation of the expression of the IFN-g response gene, Cd8, which encodes a ligand for Ccr2. The researchers proposed that expression of Ccr2 in macrophages and Cd8 in melanocytes could induce a pro-inflammatory feedback loop that could also promote melanoma growth.

This hypothesis was strengthened further with the observations that blocking IFN-g could inhibit melanoma growth in these mice and that macrophages expressing this protein were found in a majority of human melanoma samples tested. This is a particularly remarkable finding since high doses of some other interferons have been used to treat cancer, including melanoma. It indicates that, on the contrary, IFN-g may be a promising target for drug therapy in this tumour type.

Reference

Zaidi, M.R., Davis, S., Noonan, F.P. and 13 others (2011). Interferon-g links ultraviolet radiation to melanomagenesis in mice. Nature