Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment.
Author Interview: Edward C. De Fabo, Ph.D.
George Washington School of Medicine and Health Sciences
DermatologistsBlog.com: What are the main findings of the study?
Our paper shows the existence of two independent pathways to cutaneous melanoma: a UVA pathway and a UVB pathway.
The UVA pathway is dependent on the presence of melanin pigment whereas UVB is pigment independent. This was done using a transgenic mouse model of melanoma which recapitulates significant aspects of human disease.
We also found that, while UVB caused DNA damage through well-known direct mechanisms, an interaction between UVA and melanin caused indirect photo-oxidative DNA damage, further supporting a two pathway model for UV melanoma.
We also found that, in the absence of UV, hyperpigmented skin developed spontaneous melanomas although less efficiently than in response to UV radiation. This observation may help explain how melanoma can develop in hyperpigmented tissue with dysregulated melanin synthesis such as skin nevi, a well-known risk factor for skin melanoma, and in sites which are not exposed to UV radiation such as the esophagus or anal-rectal tissue.
DermatologistsBlog.com: Were any of the findings unexpected?
Yes, very much so. Melanin is thought to protect against skin cancer and indeed, does to a large degree in constitutively pigmented skin in individuals born with heavily pigmented skin. In these individuals, melanin is efficiently exported to superficial keratinocytes and acts as a protective “parasol” preventing UV from reaching melanocytes. This process is, however, much less efficient in fair skin as mimicked in our melanoma animal model.
In this model, junctional melanocytes, rare in most other animal models, are transported to the epidermal/dermal junction and become vulnerable to UV exposure. Tanning or facultative pigmentation is far less UV protective than constitutive pigmentation and, as our experiments indicate, can by interaction with UVA radiation actually increase the probability of melanoma.
DermatologistsBlog.com: What should clinicians and patients take away from this study?
We have found that melanin plays a major role in experimental melanoma. These findings help explain the well-described increased risk of melanoma from exposure to UVA tanning salons and for the high melanoma risk of hyperpigmented nevi.
We have also confirmed the important role of UVB radiation in melanoma. Importantly, this study reinforces sun safety messages, notably that exposure to UV radiation from artificial sources of UV, such as emitted from sunlamps in tanning beds should be avoided. Notably, the irradiance (intensity) of UVA from tanning lamps can be up to 12 times higher than that which can be emitted from the sun.
Finally, the use of melanotropic peptides for “sunless tanning” should clearly be avoided. As predicted by our findings of spontaneous melanoma in hyperpigmented animals, users of unregulated forms of these peptides have already been reported to develop atypical nevi and melanoma.
What recommendations do you have for future research as a result of your study?
The finding of an involvement of melanin in melanoma formation opens new areas of investigation. Notably the mouse model we used expresses a transgene for a growth factor, HGF, recently confirmed to play a major role in the outgrowth of human melanoma. Thus studies are now feasible to elucidate in this model the mechanism of melanoma formation by UVA interaction with melanin and also by UVB radiation.
In a new twist, emphasis should also be given to research on the role melanin pigment may be playing in melanoma formation in nevi and in hyperpigmented tissue not normally exposed to UV. Identification of the genetic pathways regulated by the combination of UVA and melanin and by UVB should be carried out to enable preclinical translational studies for the development of new therapeutic approaches.
Better sun protection mechanisms should be developed, paying particular attention to UVA exposure.
Frances P. Noonan, M. Raza Zaidi, Agnieszka Wolnicka-Glubisz, Miriam R. Anver, Jesse Bahn, Albert Wielgus, Jean Cadet, Thierry Douki, Stephane Mouret, Margaret A. Tucker, Anastas Popratiloff, Glenn Merlino, Edward C. De Fabo. Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nature Communications, 2012; 3: 884 DOI: 10.1038/ncomms1893