Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.

Hepatocyte growth factor-overexpressing mice that harbor a deletion of the Ink4a/p16 locus (HP mice) form melanomas with low metastatic potential in response to UV irradiation. Here we report that these tumors become highly metastatic following hemizygous deletion of the Nme1 and Nme2 metastasis suppressor genes (HPN mice). Whole-genome sequencing of melanomas from HPN mice revealed a striking increase in lung metastatic activity that is associated with missense mutations in eight signature genes (Arhgap35, Atp8b4, Brca1, Ift172, Kif21b, Nckap5, Pcdha2, and Zfp869).

A melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma.

Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor.

Functional melanocortin 1 receptor Mc1r is not necessary for an inflammatory response to UV radiation in adult mouse skin.

The G-protein-coupled receptor, Mc1r, plays a major role in pigment production and has been reported to be important in the inflammatory response. We have investigated the effect of deficiency in Mc1r on UV-induced inflammation. Mice on the same genetic background were used - C57BL/6-c (albino), C57BL/6 (black), C57BL/6-Mc1r(e/e) deficient (yellow).

Non-thermal nanoelectroablation of UV-induced murine melanomas stimulates an immune response.

Non-thermal nanoelectroablation therapy completely ablates UV-induced murine melanomas. C57/BL6-HGF/SF transgenic mice were exposed to UV radiation as pups and began to develop visible melanomas 5-6 months later. We have treated 27 of these melanomas in 14 mice with nanosecond pulsed electric field (nsPEF) therapy delivering 2000 electric pulses each 100 ns long and 30 kV/cm at a rate of 5-7 pulses per second.

Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment.

Malignant melanoma of the skin (CMM) is associated with ultraviolet radiation exposure, but the mechanisms and even the wavelengths responsible are unclear. Here we use a mammalian model to investigate melanoma formed in response to precise spectrally defined ultraviolet wavelengths and biologically relevant doses. We show that melanoma induction by ultraviolet A (320-400 nm) requires the presence of melanin pigment and is associated with oxidative DNA damage within melanocytes.

Shedding light on melanocyte pathobiology in vivo.

Cutaneous malignant melanoma is rapidly increasing in the developed world and continues to be a challenge in the clinic. Although extensive epidemiologic evidence points to solar UV as the major risk factor for melanoma, there is a significant gap in our knowledge about how this most ubiquitous environmental carcinogen interacts with the largest organ of the mammalian body (skin) at the microenvironmental and molecular level. We review some recent advances that have started to close this gap.

Interferon-γ links ultraviolet radiation to melanomagenesis in mice.

Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA.

UVB and UVA initiate different pathways to p53-dependent apoptosis in melanocytes.

The incidence of cutaneous malignant melanoma (CMM) has more than doubled in the past 25 years and continues to increase at over 3% per year across all age groups (Linos et al., this issue), and invasive and disseminated melanoma in young women has increased by almost 10% since 1992 (Purdue et al., 2008).

Economic evaluation of the US Environmental Protection Agency's SunWise program: sun protection education for young children.

Objective: The SunWise School Program is a school-based sun safety education program that was developed by the US Environmental Protection Agency and aims to teach children how to protect themselves from overexposure to the sun. The objectives of this study were to assess the health benefits of the SunWise School Program and use economic analysis to determine the program's net benefits and cost-effectiveness.

Methods: Standard cost/benefit and cost-effectiveness analysis methods were used.

Deficient inflammatory response to UV radiation in neonatal mice.

Mechanisms of juvenile susceptibility to cancer are not well understood. The immune response in neonates favors nonresponsiveness or T(H)2-dominant responses, raising the question of a role for neonatal immunity in this susceptibility. We have investigated the postulate that the inflammatory response differs in neonatal and adult skin.

Initial studies on an in vivo action spectrum for melanoma induction.

Vitamin D production is initiated by exposure of 7-dehydrocholesterol in the skin to the UVB (280-320 nm) component of sunlight, resulting in the formation of photoproducts, which are subsequently metabolically activated to biologically active moieties in a series of dark reactions as described elsewhere in this symposium. Irradiation of the skin with UVB has, however, other effects not all of which are beneficial. Most notable is the initiation of skin cancer.

Arctic stratospheric ozone depletion and increased UVB radiation: potential impacts to human health.

Contrary to popular belief, stratospheric ozone depletion, and the resultant increase in solar UV-B (280-320 nm), are unlikely to fully recover soon. Notwithstanding the success of the Montreal Protocol in reducing the amount of ozone destroying chemicals into the stratosphere, the life-times of these compounds are such that even with full compliance with the Protocol by all countries, it will be decades before stratospheric ozone could return to pre-1980 levels. This raises the question, therefore, of what will happen to biological processes essential to the maintenance of life on earth which are sensitive to damage by increased UV-B radiation, particularly those involved with human health? The polar regions, because of the vagaries of climate and weather, are the bellwether for stratospheric ozone depletion and will, therefore, be the first to experience impacts due to increases in solar UV-B radiation.

Ultraviolet B but not ultraviolet A radiation initiates melanoma.

Cutaneous malignant melanoma is one of the fastest increasing cancers with an incidence that has more than doubled in the last 25 years. Sunlight exposure is strongly implicated in the etiology of cutaneous malignant melanoma and the UV portion of the sunlight spectrum is considered responsible. Data are, however, conflicting on the roles of ultraviolet B [UVB; 280-320 nanometers (nm)] and ultraviolet A (UVA; 320-400 nm), which differ in their ability to initiate DNA damage, cell signaling pathways and immune alterations.

Mice with genetically determined high susceptibility to ultraviolet (UV)-induced immunosuppression show enhanced UV carcinogenesis.

To assess the premise that genetically determined differences in susceptibility to UV-induced immunosuppression are reflected in UV carcinogenesis, we investigated UV skin cancer induction in two strains of reciprocal F1 hybrid mice CB6F1 males with high susceptibility to UV immunosuppression and a BALB/c X-chromosome and B6CF1 males with low susceptibility to UV immunosuppression and a C57BL/6 X-chromosome. Four experimental groups comprising both strains treated three times weekly with two UV regimens (daily doses incremented from 2.25 to 6 or 4.

Immunotoxic effects of cis-urocanic acid exposure in C57BL/6N and C3H/HeN mice.

Exposure to ultraviolet radiation results in increased levels of intradermal cis-urocanic acid (cUCA) and alters cutaneous immunity by interfering with processing and presentation of antigen by Langerhans cells. Reports on effects of systemic immunotoxicity with 30 day cUCA exposure in laboratory rodents include thymic atrophy, thymic hypocellularity and decreased T-cell-mediated immunity; however, immune effects of single exposure or 5 day cUCA administration, which may better mimic human exposures, are poorly defined. The present study initially evaluated immune effects of single, 5 day, and 4 week cUCA exposure in C57BL/6N mice.

Animal models of melanoma: an HGF/SF transgenic mouse model may facilitate experimental access to UV initiating events.

Cutaneous malignant melanoma, the most lethal of the skin cancers, known for its intractability to current therapies, continues to increase in incidence, providing a significant public health challenge. There is a consensus that skin cancer is initiated by sunlight exposure. For non-melanoma skin cancer there is substantial evidence that chronic exposure to the ultraviolet B radiation (UVB) (280-320 nm) portion of the sunlight spectrum is responsible.

Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis.

Cutaneous malignant melanoma (CMM), already known for its highly aggressive behavior and resistance to conventional therapy, has evolved into a health crisis by virtue of a dramatic elevation in incidence. The underlying genetic basis for CMM, as well as the fundamental role for UV radiation in its etiology, is now widely accepted. However, the only bona fide genetic locus to emerge from extensive analysis of CMM suppressor candidates is INK4a/ARF at 9p21, which is lost frequently in familial and occasionally in somatic CMM.