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Photobiology and genetics of malignant melanoma
Abstract
The current state of knowledge of melanoma genetics is reviewed. Mutations in the tumour suppressor gene CDKN2A and in the oncogenes N-ras and H-ras seem to play the most important roles in the development and progression of malignant melanoma. Experimental studies to determine the role of ultraviolet (UV) light in the induction of melanoma have been hampered by a lack of suitable animal models. The commonly used laboratory animals are not susceptible to the induction of melanoma upon exposure to UV radiation (UVR) alone. Recent observations with four different animals have suggested, however, that UVR may be involved in the induction of melanoma. The most recent model consists of human skin grafted onto immunodeficient mice. To date, using this model, only the combination of UVB (280-320 nm) exposure and topical promoter treatment has led to the development of malignant melanoma. The wavelength dependency of the induction of melanoma has been established in the fish model Xiphophorus. The application of such an action spectrum to humans looks possible.
... It has generally been accepted that exposure to ultraviolet (UV) radiation is a main cause of skin cancer [3]. More importantly, epidemiological evidence has documented genetic variations in cancer-related genes are major contributing factors for this malignancy [4,5]. Despite the previous efforts, the pathogeneses of this disease remains unclear. ...
The objective of this study was to test the hypothesis that p53 Arg72Pro polymorphism may contribute to an increased risk of cutaneous melanoma (CM).
By searching the databases of PubMed, EMBASE, and Web of Science, a total of 8 eligible case-control studies with 1,957 CM cases and 2,887 controls were included in this meta-analysis. Stata software was used to analyze all the statistical data.
The pooled data by a fixed-effects model suggested an increased risk of CM associated with p53 Arg72Pro polymorphism under the genetic model of Arg/Pro vs. Pro/Pro without heterogeneity (ORArg/Pro vs. Pro/Pro = 1.76, 95% CI = 1.55-1.99, Pheterogeneity = 0.075). A similar trend was seen in subgroups of hospital-based studies and population-based studies.
Our meta-analysis based on all studies shows that the p53 Arg72Pro polymorphism may increase individual susceptibility to CM, particularly in Caucasians and could serve as a biomarker to predict the population at high risk of CM.
... Total regression occurs in about 5 % of the tumours, while partial regression is seen in 10-50 % of the tumours depending on their thickness (Blessing, 1992). On the genetic level, it seems that mutations in or loss of the CDKN2A (INK4a) locus and mutations in the oncogenes H-ras and N-ras play the most important roles in the development and progression of malignant melanoma (Herbst, 1997;Healy, 1996;Ortonne, 2002). The ...
... Mutations in the tumor suppressor gene CDKN2A and the oncogene N-ras and H-ras are known to be associated with the development of melanoma. [1] According to recent studies in molecular biology, the mutation of BRAF-gene kinase also plays a role in its development. [2] Metastatic melanoma to mandible is very rare. ...
Malignant melanoma is a neoplasm that arises from melanocytes or melanocytic lesion. It occurs on oral mucosa as a primary lesion or as a metastatic lesion from other organs. It usually metastasizes to the lymph node, lung, and brain. Metastatic melanoma primarily arising from other organs and spreading to the mandible is very rare so its treatment modality is not established yet. Surgery, chemotherapy, radiotherapy, and immunotherapy are applied in various ways but survival rate is still low. General condition of the patient, age, site and number of metastasis, and patient's will to treat must be considered when treating complicated patients.
We report a case of metastatic malignant melanoma which primarily arose from the left great toe and metastasized to mandible and a review of previous reports and recent treatment modalities of metastatic melanoma.
... Exposure to UV radiation can have severe consequences on both the skin and hair. Consequences on skin include erythema (also called sunburn), ageing (9-11), wrinkles (12), dryness, immunodeficiency (13)(14)(15)(16), allergies, pigmentation (also called tanning) (17)(18)(19)(20)... but also skin cancers (21)(22)(23)(24)(25)(26)(27); consequences on hair include protein and lipid oxidation, and alterations of the cosmetic aspect (appearance), structure, function, and properties (fragility) (28)(29)(30). ...
The L'Oréal group includes 17 global brands, some of which propose lines of high-grade sunscreens. Research on the biological and chemical effects of ultraviolet (UV) radiation on the skin and hair is of paramount importance to assess the efficacy of cosmetic UV filters. UV irradiances and daily doses are provided by the Tropospheric Emission Monitoring Internet Service, which is managed by the National Dutch Meteorological Institute. The data and the quality of service have been assessed. Comparisons with available data, even if limited, showed excellent agreement. A few requirements remain to be addressed, particularly data on UV-A radiation. They will be implemented within the existing user-friendly interface. All these data will be used to improve the customization of sunscreens to consumers' needs while answering health authorities' demands.
... For CMM, there are studies supporting both UVA and UVB as the main cause. It seems that mutations in the tumour suppressor gene CDKN2A and in the oncogenes N-ras and H-ras are the most important cause for developing CMM and that UVR may have a major role in inducing these mutations although the action spectrum is still unknown [26]. Setlow et al. showed in a fish model that it was mainly UVA that was responsible for the induction of CMM [27], and other studies support that hypothesis [28, 29], while de Fabo et al. showed in a mouse model that only UVB initiated CMM [30]. ...
... Exposure to UV radiation leads not only to skin photodamage 1 but, more importantly, to immunosuppression 2 and skin cancers 3 such as squamous cell carcinoma, 4 basal cell carcinoma, 5 and melanoma. 6,7 To reduce the incidence of UV-related skin cancers, the American Academy of Dermatology recommends, among other measures, the generous application of a ''broad-spectrum, water-resistant sunscreen with sun protection factor (SPF) of at least 30 to all exposed skin.'' 8 Many studies have shown that sunscreens can protect from UV-induced damage and skin cancer. ...
Background:
The manner in which consumers apply sunscreens is often inadequate for ultraviolet protection according to the labeled sun protection factor (SPF). Although sunscreen SPFs are labeled by testing at an application density of 2 mg/cm(2), the actual protection received is often substantially less because of consumer application densities ranging from 0.5 to 1 mg/cm(2). High-SPF sunscreens may provide more adequate protection even when applied by consumers at inadequate amounts.
Objective:
We sought to measure the actual SPF values of various sunscreens (labeled SPF 30-100) applied in amounts typical of those used by consumers.
Methods:
Actual SPF values were measured on human volunteers for 6 sunscreen products with labeled SPF values ranging from 30 to 100, applied at 0.5, 1.0, 1.5, and 2.0 mg/cm(2).
Results:
There was a linear relationship between application density and the actual SPF; sunscreens with labeled SPF values of 70 and above provided significant protection, even at the low application densities typically applied by consumers. Sunscreens labeled SPF 70 and 100 applied at 0.5 mg/cm(2) provided an actual SPF value of, respectively, 19 and 27.
Limitations:
The study was conducted in a laboratory setting under standardized conditions and results are extrapolated to actual in-use situations.
Conclusion:
Sunscreens with SPF 70 and above add additional clinical benefits when applied by consumers at typically used amounts, by delivering an actual SPF that meets the minimum SPF levels recommended for skin cancer and photodamage prevention. In contrast, sunscreens with SPF 30 or 50 may not produce sufficient protection at actual consumer usage levels.
... Exposure to sunlight plays a role in the development of melanoma. The incidence of melanoma per unit of surface area is higher on sun-exposed than non sun-exposed skin [1] and melanoma may be induced in animal models following ultraviolet light (UV) exposure [2]. Intermittent sun exposure has been observed as a risk factor for melanoma in many345 studies, and many are now evaluating genetic risk in combination with UV exposure, the major environmental factor. ...
Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one.
We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed.
Only the BsmI variant was associated with multiple primary melanoma (OR=1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high.
These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR.
... This observation strongly suggests that one of the major targets harmed by UVR is DNA. By contrast, the melanoma action spectrum is unknown, although some believe longer wavelengths (UVA) are relatively more important than they are for squamous cell carcinoma (Wang et al. 2001; Ortonne 2002). Three factors contribute to the optical properties of UVR transmission through the epidermis (Young 1997): melanin pigmentation, the presence of amino acids, and light scattered by melanin and amino acids. ...
Humans vary >100-fold in their sensitivity to the harmful effects of ultraviolet radiation. The main determinants of sensitivity are melanin pigmentation and less-well-characterized differences in skin inflammation and repair processes. Pigmentation has a high heritability, but susceptibility to cancers of the skin, a key marker of sun sensitivity, is less heritable. Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence. MC1R encodes a 317-amino acid G-coupled receptor that controls the relative amounts of the two major melanin classes, eumelanin and pheomelanin. Most persons with red hair are homozygous for alleles of the MC1R gene that show varying degrees of diminished function. More than 65 human MC1R alleles with nonsynonymous changes have been identified, and current evidence suggests that many of them vary in their physiological activity, such that a graded series of responses can be achieved on the basis of (i) dosage effects (of one or two alleles) and (ii) individual differences in the pharmacological profile in response to ligand. Thus, a single locus, identified within a Mendelian framework, can contribute significantly to human pigmentary variation.
... Skin cancer is one of the most prevalent types of cancers whose primary cause is chronic exposure to the UVB range (290-320 nm) of the spectrum (1). Ultraviolet B radiation is considered to be a complete carcinogen, acting as an initiator and a promoter (2) as well as an agent of tumor progression (3). The tumorigenic potential of UVB radiation is also attributed to its ability to generate highly reactive short-lived oxygen free radicals (4). ...
The main cause of skin cancer and photo-aging is chronic exposure to ultraviolet B (UVB) radiation. Such damage can be ameliorated by retinoid treatment. UVB-radiation-induced skin carcinogenesis is associated with the induction of activator protein 1 (AP1) signaling and factors, namely FOS and JUN family members. We investigated the effects of several retinoids, all-trans-retinoic acid (tRA), 9-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl)-retinamide (HPR), on UVB-induced damage in primary mouse keratinocytes. In addition, the interplay between UVB radiation, retinoid receptors, and AP1 signaling was assessed using Western blot analysis and ribonuclease protection and gene reporter assays. Exposure of keratinocytes to UVB radiation caused a down-regulation of the retinoid receptor protein levels in a proteasome-mediated manner. In contrast, FOS and JUN proteins were transiently induced shortly after exposure to UVB radiation. Retinoid treatment caused a dose-dependent reduction in the levels of retinoid receptor proteins. When irradiated cells were treated with retinoids, no significant effects on AP1 protein expression were noted. Interestingly, pretreatments with tRA and cRA, but not HPR, suppressed UVB-radiation-induced AP1 activity by more than 50%, whereas post-treatment failed to produce similar effects. Our findings indicate that the inhibition of AP1 activity by retinoids explains, at least in part, the chemopreventive potential of retinoids in UV-radiation-associated epidermal damage.
... [6][7][8][9][10] Recent advances in molecular genetics have emphasized the role of CDKN2A (p16) suppressor gene in melanoma development. [11][12][13] However, germline mutations of p16 have been detected only in patients with familial melanoma, especially from families with many affected individuals. In addition, the presence of mutations in another gene, namely the BRAF gene, has been demonstrated in a large number of melanomas and naevi, highlighting its possible implication in the initiation of melanocytic neoplasia. ...
Some studies have shown that cutaneous and mucosal melanoma biopsy specimens harbour human papillomavirus (HPV), suggesting that this virus may play a role in development and progression of the tumour.
To investigate the presence of HPV DNA and the prevalence of different high-risk mucosal HPV genotypes in primary melanoma (PM) and in acquired dysplastic melanocytic naevi (ADMN).
Fifty-one PMs from 18 men and 33 women (median age 55.5 years), 33 ADMN from 15 men and 18 women (median age 35.1 years) and 20 control skin samples from nine men and 11 women (median age 43.5 years) were studied. All diagnoses were made after histological analysis. HPV DNA analysis was made using two different polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) methods, namely MY-PCR and GP-PCR.
Using GP-PCR, mucosal HPVs were detected in 14 PMs (27%; P = 0.0166) and eight ADMN (24%; P = 0.0367), while with MY-PCR, mucosal HPVs were found in 11 PMs (22%; P = 0.04) and five ADMN (15%; P not significant). All control skin samples were negative for mucosal HPVs with both DNA amplification procedures.
Using our PCR-ELISA methods, the detection of mucosal high-risk HPV genotypes in 24% of precursor lesions (ADMN) and in 27% of PMs adds to the body of evidence indicating a colocalization of mucosal HPV and tumoral melanocytic pathologies.
Skin cancer is the most common form of cancer, accounting for 40–50% of all cancers diagnosed in the United States (Sample and He, Photodermatol Photoimmunol Photomed 34:13–24, 2017) and the incidence continues to increase worldwide. In 2012, the estimated occurrence for nonmelanoma skin cancers (NMSC) was 5.4 million cases among 3.3 million people and the American Cancer Society estimates that 99,550 cases of other skin cancer, primarily melanoma, will occur in 2018 leading to 9320 deaths from melanoma (2018). While the incidence of the majority of cancers is currently declining, the epidemic of skin cancer continues (Lazovich et al., Cancer Epidemiol Biomark Prev 21:1893–1901, 2012). With the continuing rise in incidence, there is an extensive impact of morbidity and health care costs. The estimated annual health care cost for treating skin cancer exceeds $8.1 billion demonstrating a 126% rise in cost from 2006 to 2011 while other cancers increased by 25.1% (Jemal et al., J Am Acad Dermatol 65:S17–25.e11–13, 2011; Guy et al., Am J Prev Med 48:183–187, 2015).
Familial melanoma represents approximately 10% of all melanomas. In patients with hereditary melanoma, the onset of the disease is at a young age (below 40), and the incidence of multiple melanomas is relatively high (30%). The most commonly mutated gene in familial melanoma is the cdkn2a gene (germline mutations in 30–50%), which encodes for two different proteins, P16INK4a and P14ARF, and is a key regulator of the cell cycle. Another high penetrance gene identified in melanoma is cdk4, which is involved in cell cycle progression. However, cdk4 germline mutations are rare and play a minor role in hereditary melanoma. Some low penetrance genes have been described in melanoma, including DNA repair genes such as ercc1 or xrcc3, and pigmentation genes such as mc1r. While specific variants of the mc1r gene have been associated with an increased risk for melanoma, conflicting data exist on other potential low penetrance genes regarding their role in the susceptibility to melanoma. Genetic testing of familial melanoma patients is generally not recommended.
The malignant melanoma is an immunogen malignant tumour. The thickness of the melanoma at the time of the initial diagnosis is crucial to the prognosis. Ulcerated and amelanotic melanomas still present a considerable clinical challenge due to the likelihood of being mistaken for benign diseases and the risk of metastases when diagnosis is carried out too late. We report on a 82-year-old patient with an ulceration of the foot, which was treated over a period of 5 years as a neuropathic diabetic foot ulcer. In a biopsy a malignant melanoma was detected. We were able to diagnose an invasive growing, ulcerated malignant melanoma with a tumour thickness of >4 mm according to stage III A, T4b, N2b, Mx due to AJCC classification. A sentinel-lymph-node excision was carried out and demonstrated metastases. The continuative computertomographic staging and therapy were declined by the medical attendant because of reduced general condition of the elderly patient. Our case report demonstrates the importance of differential diagnostic consideration of neoplasia, for example the malignant melanoma, in cases of unclear, therapy-refractory wounds and discusses the relevant aspects in avoiding an unnecessary prolongation of diagnostics.
The existence of UV-radiation is known since about 200 years, starting with the pioneering work of Johann Wilhelm Ritter [1]. Since then an enormous amount of knowledge has been collected about this kind of non-ionizing radiation and its impacts on nearly every part of animated and in-animated material, because the main source of environmental UV is the sun. A picture is emerging now, that solar UV-radiation, although necessary in having driven the evolution of many biological systems [2], has to be seen as one of, if not the most prominent environmental challenge presented to many organisms on earth. UV-radiation (280–400 nm) can be absorbed by many molecular components in the cell. Energies of different parts of the solar UV-spectrum (UVC: 100–280 nm, UVB: 280–315 nm, UVA: 315–400 nm) are therefore able to excite molecules to reactive electronic states which are photophysical precursors of a plenitude of photochemical reactions, depending on the UV-wavelength region. This may lead to changes in molecular structure or even create new molecular species with high and often hazardous reactivity against important molecular and genetic components in the cell. In this way cells might be damaged in an UV-dependent way. The main target of UV-induced damage in the cell is DNA. This is because DNA is able, both, to absorb UV-photons directly or to interact with UV-induced cellular species (e.g. reactive oxygen species, ROS). Both reaction pathways may introduce lesions into DNA, which if not, not fully or misrepaired may give rise to mutations with cancerogenic potential.
The incidence of cutaneous melanoma has increased worldwide in the last 20 years. Research on potential risk factors, both environmental and genetic, has led us to some new and interesting conclusions. Ultraviolet radiation is clearly the main environmental risk factor for melanoma, but its relationship is complex and controversial. With regard to genetic factors, the discovery of two types of genes was a great advance in further understanding the biology of the melanocyte. CDKN2A (p16) is the prototype of the high-penetrance, low-prevalence gene related to melanoma. This gene has been studied in some families in which several members have been diagnosed with melanoma. In the general population with non-familial melanoma, low-penetrance, high-prevalence genes such as MC1R seem to be more interesting. Studies on the MC1R gene have not only shown its importance in skin and hair pigmentation, but also in the development of melanoma. Functional studies on CDKN2A and MC1R have led us to new and important conclusions. The analysis of data from studies on families, twins and control cases, with the collaboration of several countries, will lead us to new discoveries. For the primary and secondary prevention of this tumor, we must promote public health campaigns on the dangers of sun exposure and the identification of individuals at high risk.
Skin cancer is the most common malignancy in the world. One out of three new cancers is a skin cancer (Diepgen and Mahler
2002). More than one million cases of non-melanoma skin cancer (NMSC) (basal cell carcinoma [BCC] and squamous cell cancers
[SCC]) occur annually (Jemal et al. 2008). Approximately 800,000 of these cancers are BCC and about 200,000 are SCC (Diepgen
and Mahler, 2002). In Australia, NMSC accounts for 75% of all cancers and is 30 times more prevalent than lung cancer among
men and ten times more prevalent than breast cancer among women (Burton 2000). Incidence rates for NMSC are increasing. An
average increase of 3–8% per year since the 1960s has occurred in the white populations of Europe, the United States (US),
Canada and Australia (Glass and Hoover 1989; Green 1992). Incidence data for NMSC are sparse because traditional cancer registries
do not track NMSC, however it has been estimated that the incidence of NMSC is 18–20 times greater than that of melanoma.
Incidence rates of NMSC increase proportionally with the proximity to the equator, with high cumulative Ultraviolet radiation
(UVR) light exposure and with age (Diepgen and Mahler 2002). The incidence of NMSC has until most recently affected the older
population — especially men who have worked outdoors, however the age of onset has steadily decreased. While the incidence
rates for non-melanoma skin cancers continues to rise the mortality rate has decreased in recent years however there continues
to be a substantial impact on morbidity, health and health care costs. In 2001, approximately 2,000 deaths were reported due
to NMSC mostly due to metastasis of SCC to the lymph nodes and other sites. Early diagnosis and appropriate therapy result
in a 95% cure rate. Prevention is the key management tool for NMSC.
Case Report:
A 77-year-old female patient with an ulceration of the heel is described, which was treated over a period of 2 years as a neurotrophic ulcer related to diabetes mellitus. After the initial examination in the outpatient wound healing clinic, a malignant melanoma already showing invasive growth with a penetration depth of 4.6 mm was detected in a biopsy. After diagnosis and exclusion of metastases, a phase-adapted complete excision was carried out. Furthermore, an adjuvant immunotherapy was introduced.
Conclusion:
Malignant melanoma is a primary cutaneous malignant tumor. Its thickness at the time of the initial diagnosis is crucial to the prognosis. Ulcerated and amelanotic melanomas still present a considerable clinical challenge due to the likelihood of being mistaken for benign diseases and the occurrence of filiae when diagnosis is made too late. This case report demonstrates the importance of differential diagnostic consideration of neoplasias, for example malignant melanoma, in cases of unclear, therapy-refractory wounds and discusses the relevant aspects in avoiding an unnecessary prolongation of diagnostics.
Men have a higher lifetime incidence of melanoma than women.
Data from the 2005 Health Interview Survey were analyzed for sex differences in response to sun exposure and reported preventive measures among adults.
There were 31,428 people surveyed representing the US population. Although women were more likely to burn after 1 hour of sun (8.7% vs 5.4%), they also reported fewer sunburns than men (mean .7 vs .9). Women were also more likely stay in the shade (11.2% vs 6.2%) and always use sunscreen. However, women used a tanning bed more than men (2.1 vs .6 times per year) and were less likely to wear protective clothing when in the sun than men. After controlling preventive behaviors, men were 1.4 times more likely to have had a sunburn during the last 12 months.
Although men more often wear protective clothing and are less likely to use a tanning bed, women are more likely to avoid sun exposure and use sunscreen. The higher incidence of melanoma in men may be explained, in part, by an increased incidence of preventive measures taken by women.
Oral ingestion of green tea is a potent dietary source of antioxidant polyphenols. These compounds are of interest as they may be able to provide additional protection to the body to help prevent the deleterious effects of ultraviolet A and visible radiation (UVA/VIS) produced indirectly via reactive oxygen species (ROS) in sunlight exposed skin. A small clinical study was conducted in ten healthy adult volunteers. Samples of whole blood were obtained from each before and 30, 60 and 90 min following ingestion of three breakfast cups of green tea (540 ml in total) prepared in a standardised manner. Peripheral leucocytes were isolated from each blood sample and exposed to increasing periods of UVA/VIS irradiation in the laboratory (0, 9, 12 or 18 min). Alkaline single cell gel electrophoresis (the comet assay) was then conducted to determine the level of DNA damage in each sample from each individual. The findings support those of our previous pilot study and indicate that drinking green tea did significantly reduce the genotoxic effects observed in peripheral blood cells 60 min following ingestion when artificially exposed to 12 min of UVA/VIS irradiation in the laboratory. It is postulated that this protection is afforded by the polyphenol compounds (known to be contained within green tea) via scavenging or quenching of the damaging ROS induced by this form of light exposure. Further investigation should consider whether this dietary-induced protection could be extended to cells of the skin.
CASE REPORT: A 77-year-old female patient with an ulceration of the heel is described, which was treated over a period of 2 years as a neurotrophic ulcer related to diabetes mellitus. After the initial examination in the outpatient wound healing clinic, a malignant melanoma already showing invasive growth with a penetration depth of 4.6 mm was detected in a biopsy. After diagnosis and exclusion of metastases, a phase-adapted complete excision was carried out. Furthermore, an adjuvant immunotherapy was introduced. CONCLUSION: Malignant melanoma is a primary cutaneous malignant tumor. Its thickness at the time of the initial diagnosis is crucial to the prognosis. Ulcerated and amelanotic melanomas still present a considerable clinical challenge due to the likelihood of being mistaken for benign diseases and the occurrence of filiae when diagnosis is made too late. This case report demonstrates the importance of differential diagnostic consideration of neoplasias, for example malignant melanoma, in cases of unclear, therapy-refractory wounds and discusses the relevant aspects in avoiding an unnecessary prolongation of diagnostics.
The multiple molecular alterations underlying the neoplastic process and clinical characteristics of cutaneous melanoma are currently under intensive investigation. Recent studies have demonstrated that the levels of melanoma-associated proteins in tumor tissue or in patient serum can serve as new markers to predict disease outcome. Similarly, the expression of thousands of genes in melanoma tumors can be surveyed simultaneously using DNA arrays, allowing molecular profiling of individual tumors, which gives the possibility of classifying melanomas based on their biological diversity. Large clinical studies have also identified multiple prognostic factors, such as tumor ulceration, and led to development of a new, more precise melanoma staging system, which emphasizes the biological characteristics of the primary disease. These new findings may have an important role in earlier measurement of the clinical response and provide a basis for tailored melanoma therapy, the development of which will also be discussed in this review.
Cutaneous photoageing is a complex biological process affecting all layers of the skin. Skin damage resulting from intrinsic ageing and extrinsic photoageing may trigger skin cancer. In patients with advanced photoageing and/or diffuse actinic damage, local therapy is often inadequate and the possibility of combined therapy needs to be assessed.
Here we report three cases of patients over 75 years of age with advanced diffuse epithelial skin damage of photoexposed areas consisting of several superficial actinic keratoses, ipermelanotic lesions and multiple skin cancers.
Neoplastic lesions and damaged skin were removed by superficial erbium laser ablation and the epidermis reconstructed with autologous epidermal sheets expanded in vitro from healthy cells obtained from unexposed areas of the body.
Our initial studies show that this procedure is very effective in the short term for treating and preventing the UV-induced skin cancer and precancerous lesions, and also suggest good long-term control of the disease with very interesting aesthetic results.
Uveal melanoma is the most frequent primary malignant intraocular tumor of adults. Among various non-modifiable risk factors, Caucasian race seems to be the most significant with light skin color, blond hair, and blue eyes being specific risk factors. The racial predisposition to uveal melanoma have been explained on the basis of susceptibility of Caucasian race to oncogenic effects of sunlight. Although there is ample evidence in support of this hypothesis in regard to skin melanoma, the evidence in regard to uveal melanoma is insufficient and contradictory. In the following review, we examine physiologic, epidemiological, and genetic data in order to determine the role of sunlight exposure in the pathogenesis of uveal melanoma.
Antioxidant compounds in green tea may be able to protect against skin carcinogenesis and it is of interest to investigate the mechanisms involved. A study was therefore conducted to determine whether the isolated green tea polyphenol (-)-epigallocatechin gallate (EGCG) could prevent ultraviolet radiation (UVR)-induced DNA damage in cultured human cells. This work was then extended to investigate whether drinking green tea could afford any UVR protection to human peripheral blood cells collected after tea ingestion.
The alkaline comet assay was used to compare the DNA damage induced by UVR in cultured human cells with and without the presence of EGCG. The same assay technique was then employed to assess UVR-induced DNA damage in peripheral leucocytes isolated from 10 adult human volunteers before and after drinking 540 ml of green tea.
Initial trials found that EGCG afforded concentration-dependent photoprotection to cultured human cells with a maximal activity at a culture concentration of 250 microM. The cells types tested (lung fibroblasts, skin fibroblasts and epidermal keratinocytes) demonstrated varying susceptibility to the UVR insult provided. The in vivo trials of green tea also demonstrated a photoprotective effect, with samples of peripheral blood cells taken after green tea consumption showing lower levels of DNA damage than those taken prior to ingestion when exposed to 12 min ultraviolet A (UVA) radiation.
The studies showed that green tea and/or some constituents can offer some protection against UV-induced DNA damage in human cell cultures and also in human peripheral blood samples taken post-tea ingestion.
Identification of specific genes or signaling pathways involved in development of melanoma could lead to new therapies that target and correct these defects. Recent studies have revealed deregulation of the Akt signaling pathway occurring in 43-67% of melanomas. Akt kinase family members, Akt1/PKBalpha, Akt2/PKBbeta and Akt3/PKBgamma, share extensive structural similarity and perform common as well as unique functions within cells. The Akt signaling cascade initiates at the cell surface when growth factors or other extracellular stimuli activate phosphoinositide 3-kinase (PI3K). Activated PI3K generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP3), causing translocation of Akt to the plasma membrane where it becomes phosphorylated and activated. The balance of cellular PIP3 is regulated primarily by a phosphatase called PTEN that reduces PIP3 levels thereby lowering Akt activity. In melanomas, decreased PTEN activity elevates PIP3 levels resulting in Akt activation. Active Akt then phosphorylates downstream cellular proteins that promote melanoma cell proliferation and survival. Recently, Akt3 was discovered to be the predominant isoform activated in sporadic melanomas. Levels of activity increased during melanoma progression with metastatic melanomas having the highest activity. Although mechanisms of Akt3 activation remain to be fully characterized, overexpression of Akt3 and decreased PTEN activity play important roles in this process. Targeted reduction of Akt3 activity decreased survival of melanoma tumor cells leading to inhibition of tumor development, which may be therapeutically effective for shrinking tumors in melanoma patients. This review surveys recent developments in Akt deregulation in melanoma and its potential as a selective therapeutic target in patients in the advanced stages of this disease.
The care of patients who have cutaneous melanoma (CM) has undergone a dramatic change during the past five decades. In an increasing majority of cases, CM is being discovered in a premetastatic phase of tumor progression. Most patients are being treated in the ambulatory setting with a minimum of inconvenience and economic cost, and modest re-excision margins have largely replaced the mutilating surgical exonerations that were once standard only four decades ago. Histopathologic assessment of the primary tumor is the most widely used staging procedure to determine who is most likely to develop metastatic disease. For patients who develop distant metastases, there is no therapy currently available, based on large-scale randomized trials, that will prolong patient survival. Therefore, establishing an early diagnosis in a premetastatic phase of tumor development must be the overriding goal of any intervention strategy that seeks to reduce CM-related mortality. Unfortunately, as a result of public messages that emphasize the role of ultraviolet radiation (UVR) exposure in tumor development, most general physicians and lay people believe that most if not all cases of CM are the direct result of UVR exposure. In fact, we do not know the case fraction of CM directly attributable to UVR, and the unintended consequences of current messages directly linking UVR exposure and CM development may be thwarting the primary intervention goal of reducing tumor-related mortality. More likely to have an immediate positive impact on CM-related mortality are public messages that encourage skin awareness and self-examination by patients, total skin screening examinations by physicians during routine care, and periodic lifetime surveillance of patients determined to have a high CM risk based on identifiable historic and phenotypic traits.
Malignant melanoma is the third most common skin cancer in the United States. It is commonly thought that sun exposure is causative in these tumors. Recently, however, the significance of the role of sun exposure in melanoma has come into question. Some have suggested that other factors, such as genetics, play a larger role, and that sun protection may even be harmful.
To investigate the role of sun exposure in melanoma etiology. An extensive review of basic science and clinical literature on this subject was conducted.
Although exceptions exist, sun exposure likely plays a large role in most melanomas. The pattern of this exposure, however, is not fully known, and controversy exists, especially in the use of sunscreens. Sun exposure may interact with genetic factors to cause melanomas, and sun protective measures appear to be prudent.
The cause of melanoma is probably variable and multifactorial. Sun exposure may play a primary or supporting role in most melanoma tumors.
During the past several decades, there has been a substantial increase in the incidence of cutaneous melanoma among all caucasian populations. The number of deaths due to cutaneous malignant melanoma has also increased in most fair-skinned populations throughout the world in the past few decades. Trends in melanoma incidence worldwide are examined. The most recent data on the mortality from cutaneous melanoma are reported. The role of different environmental, genetic and host factors in the aetiology of melanoma is discussed.
Vitamin C has been reported to be useful in the treatment and prevention of cancer. Inconsistent effects from growth stimulation to induction of apoptosis of malignant tumor cells, however, have been reported. Melanoma is an increasingly common and potentially lethal malignancy. It was reported that melanoma cells were more susceptible to ascorbate toxicity than any other tumor cells. The mechanisms accounting for ascorbate-induced apoptosis in human melanoma cells, however, have remained unclear. This study was undertaken to investigate the effect of sodium ascorbate on cytotoxicity and apoptosis in human malignant melanoma A375.S2 cells. A375.S2 cells were incubated with a certain range of concentrations of sodium ascorbate for various time periods. In order to examine the effects of sodium ascorbate on cell proliferation, cell cycle, apoptosis and necrosis, we performed 4,6-diamidino-2-phenylindole dihydrochloride assays and flow cytometry analysis. Polymerase chain reaction was used to examine the mRNA levels of p53, p21, p27, cyclin A, cyclin E, CDK2 and CDK4, which are associated with cell cycle S-phase arrest and apoptosis. Flow cytometric analysis showed that sodium ascorbate significantly induced cell cycle arrest and apoptosis in the A375.S2 cell line in a dose-dependent manner. The increased expressions of p53 and p21, and the decreased expressions of cyclin A, cyclin E, CDK2 and CDK4, indicated the cell cycle arrest at G1/S phase after the cells had been treated with sodium ascorbate. Induction of apoptosis involved an increase in the levels of p53, p21 and cellular Ca, and a decrease in mitochondrial membrane potential and activation of caspase 3 before culminating in apoptosis in sodium ascorbate-treated A375.S2 cells.
It is generally accepted that sunlight may contribute to the development of melanoma.
To analyse gene expression of melanocytes obtained from clinically unaffected skin of patients with melanoma and healthy controls before and after exposure to ultraviolet B radiation.
Using GeneChip array technology, the gene expression of melanocytes obtained from the two donor groups was profiled, in order to identify transcriptional differences affecting susceptibility to melanoma.
The data collected did not show any difference between the expression profiles of melanocytes purified from normal donors and from patients with melanoma that was able to give a statistically significant class separation. However, by means of unsupervised clustering our data could be divided into two main classes. The first class included the transcriptome profiles of melanocytes obtained from skin samples of patients with a vertical growth phase (VGP) melanoma, while the second class included the transcriptome profiles of melanocytes obtained from skin samples of patients with a radial growth phase (RGP) melanoma.
These data suggest that melanocytes in patients with VGP and RGP melanomas show significant differences in gene expression profiles, which allow us to classify patients with melanoma also from clinically unaffected skin.
p53 has a common polymorphism at amino acid 72, encoding either arginine or proline. p53Arg and p53Pro exhibit differences in various biological activities, such as cell-cycle arrest and induction of apoptosis. Numerous epidemiological studies have examined the role of this polymorphism in several human malignancies, including cutaneous cancers, with contradictory results.
To investigate the germline frequency of p53 codon 72 polymorphism in malignant melanoma in a Mediterranean population, and to examine possible associations with various clinicopathological factors.
In this hospital-based case-control study we used allele-specific polymerase chain reaction for p53 codon 72 genotyping in blood specimens from 107 Greek patients with sporadic cutaneous melanoma and 145 healthy controls.
After adjustment for age, sex and phototype the Pro/Pro genotype was associated with increased risk for cutaneous melanoma compared with the Arg/Arg genotype (adjusted odds ratio, OR 3.17, 95% confidence interval, CI 1.03-9.78). This correlation was more pronounced in subjects with phototypes III or IV (adjusted OR 9.56, 95% CI 1.56-58.46), dark skin (adjusted OR 10.96, 95% CI 1.64-73.28), dark eyes (adjusted OR 8.86, 95% CI 1.69-46.52) and dark hair (adjusted OR 3.17, 95% CI 1.01-9.95), and among noncarriers of melanocortin 1 receptor gene (MC1R) red hair polymorphisms (adjusted OR 2.99, 95% CI 1.02-8.78).
p53 codon 72 Pro/Pro genotype could be a risk factor for the development of melanoma in the Greek population, especially in subgroups with darker skin pigmentation, as well as among noncarriers of the MC1R red hair polymorphic variants.
The most common hereditary melanoma susceptibility disorder is the familial atypical multiple mole-melanoma (FAMMM) syndrome. FAMMM is regarded as an ideal natural model to study the very complex pathologic mechanism of melanoma. In 1994, cloning of the melanoma susceptibility gene CDKN2A was thought to give answers to many questions on genotype-phenotype correlations in familial melanoma. Today, 4 y later, germline mutations cosegregate with melanoma in only 40%–50% of the families predisposed to this disease. The hunt for genes and modifying genes is on again. Through the years the very well-characterized Dutch FAMMM families have proven to be valuable study subjects in melanoma research. This paper describes over 10 y of melanoma research illustrated by research performed in the Dutch FAMMM families.Keywords: CDKN2A, hereditary melanoma, melanocortin 1 receptor
Information on the variation in carcinogenicity with wavelength is crucial in risk assessments for skin cancers induced by UV radiation. Until recently the wavelength (lambda) dependencies of other detrimental UV effects, such as sunburn, have been used as substitutes. Direct information on the lambda dependency can only be obtained from animal experiments. To this end we accumulated a large data set on skin tumors induced by chronic UV exposure of albino SKH:HR1 mice (14 different broadband UV sources and about 1100 mice); the data come from the Photobiology Unit of the former Skin and Cancer Hospital in Philadelphia and from the Department of Dermatology of the University of Utrecht. The lambda dependency was extracted from this data set (a statistically satisfactory description with chi 2 = 13.4, df = 7) and represented by the Skin Cancer Utrecht-Philadelphia action spectrum, i.e., a set of factors to weight the exposures at different wavelengths according to their respective effectiveness (inversely proportional to the daily exposure required for a median tumor induction time of 300 days). The fits obtained with other already available action spectra proved to be poor (chi 2 > 60, df = 11). The maximum effectiveness was found at 293 nm, and above 340 nm the effectiveness showed a shoulder at about 10(-4) of the maximum. A sensitivity analysis of the final solution for the lambda dependency showed a large margin of uncertainty above 340 nm and an information gap below 280 nm. The large variation in tumor responses in the present data set can be transformed to a coherent, common dose-response relationship by proper spectral weighting with this single action spectrum.
The genetic basis of spontaneous melanoma formation in spotted dorsal (Sd) Xiphophorus platyfish-swordtail hybrids has been studied for decades, and is adequately explained by a two-gene inheritance model involving a sex-linked oncogene, Xmrk, and an autosomal tumor suppressor, DIFF. The Xmrk oncogene encodes a receptor tyrosine kinase related to EGFR; the nature of the DIFF tumor suppressor gene is unknown. We analyzed the gentic basis of UV-B-induced melanoma formation in closely related, spotted side platyfish-swordtail hybrids, which carry a different sex-linked pigment pattern locus, Sp. We UV-irradiated spotted side Xiphophorus platyfish-swordtail backcross hybrids to induce melanomas at frequencies 6-fold higher than occur spontaneously in unirradiated control animals. To identify genetic determinants of melanoma susceptibility in this UV-inducible Xiphophorus model, we genotyped individual animals from control and UV-irradiated experimental regimes using allozyme and DNA restriction fragment length polymorphisms and tested for joint segregation of genetic markers with pigmentation phenotype and UV-induced melanoma formation. Joint segregation results show linkage of a CDKN2-like DNA polymorphism with UV-B-induced melanoma formation in these hybrids. The CDKN2-like polymorphism maps to Xiphophorus linkage group V and exhibits recombination fractions with ES1 and MDH2 allozyme markers consistent with previous localization of the DIFF tumor suppressor locus. Our results indicate that the CDKN2-like sequence we have cloned and mapped is a candidate for the DIFF tumor suppressor gene.
Two case-control studies were set up to investigate the relationship between melanocytic naevi and risk of melanoma and to compare the naevus phenotype in two countries exposed to greatly different levels of sun exposure and different melanoma rates. In England 117 melanoma cases and 163 controls were recruited from the North-East Thames Region and 183 melanoma cases and 162 controls from New South Wales, Australia. Each subject underwent a whole-body naevus count performed by the same examiner in each country. Relative risks associated with melanocytic naevi in each country were calculated with comparison of naevus data in controls between Australia and England. Atypical naevi were strong risk factors for melanoma in both countries: the odds ratio (OR) for three or more atypical naevi was 4.6 (95% CI 2.0-10.7) in Australia compared with 51.7 (95% CI 6.5-408.4) in England. Common naevi were also significant risk factors in Australia and England with similar odds ratios in the two countries. Prevalence of atypical naevi was greater in Australian controls than in English controls: OR 9.7 (95% CI 1.2-81.7) for three or more atypical naevi in Australia compared with England. For young age groups, the median number of common naevi was greater in Australia than in the UK, whereas for older individuals this difference in naevi number between the two countries disappeared. The prevalence of naevi on non-sun-exposed sites in controls was not significantly different between the two countries. The atypical mole syndrome (AMS) phenotype was more prevalent in Australian controls (6%) than in English controls (2%). The results of this study support the role of sun exposure in the induction of atypical naevi in adults. There was a trend towards stronger risk factors associated with atypical naevi in England compared with Australia. The atypical mole syndrome, usually associated with a genetic susceptibility to melanoma, was more common in Australia than in England, suggesting genetic environmental interactions with the possibility of phenocopies induced by sunlight.
The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.
The quantitative determinations of the effects of different wavelengths or spectral regions in sunlight on skin and on molecules in skin are important not only to devise appropriate protective measures against the deleterious actions of light exposure, but also to assess the molecular bases of the effects mediated by molecular absorbers. Such absorbers include the macromolecular structures of nucleic acids, proteins, and lipids, as well as smaller, possibly key, molecules such as urocanic acid and numerous photodynamic sensitizers as well as psoralens.
The three major forms of skin cancer (melanoma, squamous cell carcinoma, and basal cell carcinoma) are all epidemic in the Caucasian population of North America, and each has therefore been the subject of numerous investigations. This chapter reviews the descriptive and analytic epidemiology of melanoma and nonmelanoma skin cancer. The data reviewed are based primarily on populations in the United States and Canada; the (largely parallel) results that characterize the Scandinavian and Australasian literature are reviewed in Chapters 9 and 10.
The genesis of the problem of skin cancer in Australia did not occur until the first European settlement in the late eighteenth century, since Aboriginal Australians are rarely affected by skin cancer. From first settlement until the midtwentieth century, inhabitants of Australia were almost entirely of British descent, with high proportions of Irish and Scots. Their migration and settlement signified a shift from northern latitudes of 51 ° to 59° to much lower southern latitudes, e.g., Sydney at 34° and Brisbane at 27°, and to a land which received up to double the annual hours of sunshine of the British Isles (Scott, 1972).
Skin cancer is a serious problem in the Scandinavian countries, as it is in most countries with white populations (Magnus, 1989, 1991; Muir and Nectoux, 1982). Scandinavia is located at high latitudes (>54°N) and therefore receives relatively small annual exposures of ultraviolet (UV) radiation from the sun. In spite of this, skin cancer (cutaneous malignant melanoma, squamous cell carcinoma, and basal cell carcinoma) is more frequent than any other cancer form.
Experimental and epidemiological data suggest a possible role for UVA in the induction of malignant melanoma. Intermediates in the melanin biosynthesis pathway may act as DNA photosensitizing agents. Further research on the possible role of UVA in malignant melanoma is urgently required.
Triplet state quenching of the ketones benzophenone, p-methylbenzophenone, p-phenylbenzophenone and benzil by silanes containing an SiH bond was investigated in a 9:1 (v/v) mixture of acetonitrile and acetone. It was found that both the n,π* and n,π*−π,π* triplet states are quenched if their energies are above 280 kJ mol−1. Quenching rate constants kH were determined using steady state phosphorescence quenching and the time-resolved measurement of the triplet—triplet absorption. From an analysis of the behaviour of the triplet—triplet absorption of benzophenone as a function of time at variable silane concentrations, a reaction scheme was derived which includes the combination reactions of diphenyl ketyl, solvent and silyl radicals and the addition of silyl radical to the ground state of benzophenone. kH values obtained in this way agree with the phosphorescence quenching data and are of the order of 3 × 106 to 3.4 × 108 dm3 mol−1 s−1. Furthermore, it was found that the log kH values depend on the magnitude of the wavenumber of the SiH vibration of the silanes.
Sho-saiko-to is the most popular herbal medicine in Japan. We investigated the anti-tumor and anti-metastatic effects of Sho-saiko-to and its chemically defined ingredients on the primary skin melanoma that developed in a metallothionein-I (MT)/ret transgenic mouse line and on a melanoma cell line (Mel-ret), which was derived from a primary tumor developed in a MT/ret transgenic mouse. In vitro, Sho-saiko-to suppressed the growth of Mel-ret cells more strongly than any single ingredient of Sho-saiko-to, although baicalin as one of several ingredients tested also suppressed it significantly. In vivo, Sho-saiko-to (i) significantly (p < 0.02) prolonged the onset of tumor development (1.5 mo), (ii) definitely retarded the transition to malignancy, (iii) significantly decreased the incidence of distant metastasis to brain (p < 0.002), kidney (p < 0.05), and liver (p < 0.05) at the malignant stage, and (iv) significantly (p < 0.02) prolonged life span (2.6 mo). Moreover, Sho-saiko-to and baicalin downregulated the matrix metalloproteinase-2 and -9 expression levels, and upregulated their inhibitor expression level in both the primary tumors and Mel-ret cells. In conclusion, Sho-saiko-to displayed anti-tumor and anti-metastatic effects on melanoma with regulation of the balance of matrix metalloproteinase and tissue inhibitor of the matrix metalloproteinase levels.Keywords: baicalin, Sho-saiko-to, matrix metalloproteinase
Transfer of genetic material into recipient cells by transfection has been used successfully to isolate genes responsible for particular phenotypic traits. By using this strategy, DNA fragments were isolated that when transfected into appropriate uncommitted cells will commit the recipient cells to undergo adipocyte differentiation. Transgenic mice were generated with one of the active DNA clones, Clone B. The transgenic mice were expected to display an adipocyte-related phenotype; however, the animals developed melanin containing tumors at a young age. Insertion of Clone B into the mouse DNA probably interrupted a gene(s) that is involved in the regulation of cell growth, specifically regulation of cell growth in melanin-producing cells. Histopathologic analysis of these mice showed dark spots on the ear lobes of the animals as early as 10-12 d of age. By 3 mo, in addition to the ear lobes, pigmented tumors could be observed in other organs. A significant number of these transgenic mice died within 1 y of age. The melanomas developed spontaneously in these animals in the absence of any known chemical carcinogen or ultraviolet radiation. This line of mice provides a way of identifying genes involved in regulation of cell growth control and differentiation. These mice also serve as a model system to investigate the molecular, genetic, and phenotypic characterization and development of melanomas.
Interest in the etiology of human malignant melanoma has increased considerably in recent years. The basis for this heightened concern can be attributed to two seemingly unrelated issues. The first is that the incidence of malignant melanoma is increasing at an alarming rate. At the present time, both the incidence of melanoma and the mortality rate are doubling every 10 to 17 years. Thus identification of causal factors in the development of melanoma is an urgent necessity if this upward trend is to be curbed. The second issue that has directed attention to the identification of etiologic factors in malignant melanoma is ozone depletion. The layer of ozone surrounding the earth shields it from solar uv radiation. Anticipated decreases in stratospheric ozone, resulting from high-altitude aircraft, nuclear explosions, and the release into the atmosphere of chlorofluoromethanes from refrigerants and aerosol sprays, raised concerns about the effects of an increased exposure of all life forms to uv light. One anticipated effect of increased exposure of humans to uv light is a corresponding increase in some types of skin cancer in humans. If malignant melanoma is included among the types of skin cancer at risk of increasing, then the impact of ozone depletion on humans is serious indeed. In the prognosis for melanoma is less favorable, particularly in cases in which the tumor is already invasive at the time of diagnosis. Thus the threat of an increased level of exposure to light has stimulated a careful reevaluation of the role of radiation in the induction of melanoma.
Ocular and cutaneous melanomas arose in new inbred lines of transgenic mice having an integrated recombinant gene comprised of the tyrosinase promoter, expressed in pigment cells, and the simian virus 40 early-region transforming sequences. The tumors were hypomelanotic and were histopathologically similar to corresponding human melanomas. Eye melanomas often originated at a young age, chiefly from the retinal pigment epithelium, also from the choroid, and rarely from the ciliary body. The eye tumors grew aggressively, were highly invasive, and metastasized to local and distant sites. The earliest formation of these tumors was associated with higher copy numbers of the transgene; mice of different single-copy lines varied greatly in age of onset and frequency of eye tumors. Coat pigmentation was reduced in almost all lines, to various extents. Primary skin melanomas arose later and less frequently than eye melanomas. Hence they were at early stages and of unknown long-range incidence in this investigation, in which autopsies covered the first half-year of life. For both ocular and cutaneous melanomas, the transgenic mice offer numerous possibilities for experimental study of mechanisms underlying formation and spread of melanomas.
A total of 19 male and 21 female South American opossums (Monodelphis domestica) were exposed to 250 J/m2 ultraviolet radiation from FS-40 sunlamps (280-400 nm) three times weekly for 70 weeks. The backs of the opossums were shaved as necessary to remove hair. In order to prevent photoreactivation of ultraviolet radiation-induced pyrimidine dimers by the light-dependent photolyase enzyme of the opossum, ultraviolet radiation-exposed opossums were housed under red lights (600-800 nm). The opossum photolyase requires light in the 320-450 nm range for its activity. Twenty-nine control opossums (14 males and 15 females) were irradiated by fluorescent lights with emission spectra primarily in the visible light range (320-700 nm); these control opossums were also housed under red lights, and their backs were also shaved to remove hair. No skin tumors were observed in control opossums, while ultraviolet radiation-exposed opossums developed a variety of hyperplastic and neoplastic skin lesions on the backs and on a single ear. Hyperplastic lesions included foci of epithelial hyperplasia, dermal fibroplasia, and focal proliferation of dermal melanocytes. A total of 20 ultraviolet radiation-exposed opossums (50%) developed skin tumors, and 13 opossums (32.5%) had more than a single tumor. Epithelial tumors included 25 papillomas, four keratoacanthomas, seven carcinomas in situ, three microinvasive squamous cell carcinomas, two invasive squamous cell carcinomas, and a single basal cell tumor. Ten dermal spindle cell tumors also occurred; most of these appeared to be fibrosarcomas. Two benign melanomas and one malignant melanoma were observed.
Several lines of evidence support the hypothesis that ultraviolet radiation (UVR) is involved in the etiology of cutaneous melanoma in humans. However, progress in understanding the mechanisms involved in induction of melanotic tumors by UVR has been hindered by lack of a suitable animal model. During the course of multiple exposures (3 times/wk for 70 wk) of the South American opossum, Monodelphis domestica, to UVR, we first observed the appearance of areas of dermal melanocytic hyperplasia (MH) on the exposed skin. Post-UVR exposure to photoreactivating light (320-500 nm) suppressed the occurrence of MH. We also observed at 100 weeks from first exposure that 10 of 46 surviving animals had developed melanotic tumors which arose, presumably, from areas of MH. Tumors on three of the 10 animals have been classified as malignant melanomas based on metastasis to lymph nodes. We conclude from these results that UVR can act as a complete carcinogen for melanoma induction and, based on the photoreactivation of MH induction, that DNA damage is involved in melanoma formation.
The action spectra for delayed erythema and melanogenesis in Caucasian human skin are determined for wavelengths between 250 and 435 nm. The untanned skin of very fair volunteers was observed after single exposures to a range of fluences of monochromatic radiation. At wavelengths longer than 300 nm the two action spectra are indistinguishable, and at wavelengths shorter than 300 nm, they are of similar shape despite a distinct separation. This suggests a common or similar chromophore for initiation of the vascular and pigmentary responses to UV. A broad minimum in the action spectra occurs near 280 nm, a maximum near 296 nm, and for wavelengths longer than 300 nm, increasingly larger fluences of radiation are required to induce delayed erythema and melanogenesis. Between 304 and 334 nm both action spectra exhibit a rapid decrease of almost three orders of magnitude. In contrast, between 334 and 405 nm the spectra decrease by only one order of magnitude, and there is a suggestion of a small maximum at or near 365 nm. Different chromophores, sites of damage, or response mechanisms may be responsible for induction of delayed erythema at these longer wavelengths. After spectral corrections for the optical effects of the stratum corneum, the shape and magnitude of the action spectra are grossly consistent with a mechanism in which DNA is the primary chromophore initiating the response pathways for wavelengths less than 313 nm. Whatever the actual basis for these action spectra may be, they are of practical significance in predicting skin response to sources of ultraviolet radiation.
A new mouse model of UV radiation-induced melanoma is described. Unlike previous models, melanoma induction requires only short-term irradiation, does not require the application of chemical carcinogens, and does not cause any other tumors. The model takes advantage of the fact that Tyr-SV40E (C57BL/6 strain) transgenic mice are all melanoma-susceptible, and that different inbred lines are susceptible to different extents. Four-day-old mice of a moderately susceptible line (line 9 transgenic homozygotes) were exposed for 20 min/day to 328 mJ/cm2 to UVB (280-320 nm wavelength, comprising 70% of the total irradiance) for up to 4 consecutive days. Melanocytic lesions resembling macules, nevi, or early melanomas gradually appeared in the irradiated mice that were not seen in unirradiated transgenic controls of similar age. To afford ongoing observation beyond the short life span of line 9 homozygous mice, skin samples containing a total of 26 selected lesions were grafted at 20 weeks after UV radiation to longer-lived unirradiated hosts of transgenic line 12, in which melanoma susceptibility is low. Ten lesions in the grafts became melanomas; all melanomas had ulcerated and two had metastasized. At the stages examined, all the tumors were deeply melanotic. The remaining 16 lesions were still indolent when the experiment was terminated at 57 weeks post-UV radiation. The present protocol lends itself to variations in the choice of transgenic line, the age of the treated mice, and the intensity and duration of ultraviolet light; appropriate combinations of these variables would be expected to yield melanomas in relatively long-lived transgenic mice without skin grafting. The new model provides an opportunity to determine the melanoma action spectrum, to characterize at the molecular level the melanomas induced by ultraviolet light in comparison with those of other origins, and to investigate in vivo the photoprotective role of melanin.
The wavelength dependency of carcinogenesis is an important factor in risk assessments pertaining to sources of ultraviolet radiation, the most important of which is the sun. This wavelength dependency cannot be measured directly in humans, but it has been measured in hairless mice, and represented in an action spectrum. An estimate of the action spectrum for humans can be produced by correcting for differences in epidermal transmission between mice and humans. This carcinogenic action spectrum for humans resembles the action spectrum for ultraviolet-induced erythema (sunburn), and results in small adjustments of earlier estimates of the effects of a stratospheric ozone depletion on skin cancer incidences.
It is generally agreed that sunlight exposure is one of the etiologic agents in malignant melanoma of fair-skinned individuals. However, the wavelengths responsible for tumorigenesis are not known, although DNA is assumed to be the target because individuals defective in the repair of UV damage to DNA are several thousandfold more prone to the disease than the average population. Heavily pigmented backcross hybrids of the genus Xiphophorus (platyfish and swordtails) are very sensitive to melanoma induction by single exposures to UV. We irradiated groups of five 6-day-old fish with narrow wavelength bands at 302, 313, 365, 405, and 436 nm and scored the irradiated animals for melanomas 4 months later. We used several exposures at each wavelength to obtain estimates of the sensitivity for melanoma induction as a function of exposure and wavelength. The action spectrum (sensitivity per incident photon as a function of wavelength) for melanoma induction shows appreciable sensitivity at 365, 405, and probably 436 nm, suggesting that wavelengths not absorbed directly in DNA are effective in induction. We interpret the results as indicating that light energy absorbed in melanin is effective in inducing melanomas in this animal model and that, in natural sunlight, 90-95% of melanoma induction may be attributed to wavelengths > 320 nm--the UV-A and visible spectral regions.
1996 Imperial Cancer Research Fund. Melanomas occur naturally or may be induced experimentally in many animals (reviewed in Kripke, 1979; Pawlowski and Lea, 1983; Beattie et al, 1988; Epstein, 1992; Ingram, 1992; Mukhtar and Bickers, 1993; Dooley, 1994; Clark, 1994; Ley, 1995b). The aetiology, behaviour, and appearance of these tumours vary considerably among species. Thus, the extent of similarity between animal and human melanomas is also quite variable. No animal model, however, precisely mimics all features of human melanoma. Spontaneous melanoma is generally rare in animals, except for Sinclair swine and some Xiphophorus hybrids. In most animal models, melanoma must be induced by chemical carcinogens. Only in three animals - Xiphophorus hybrids, transgenic mice and the opossum, Monodelphis - is UVR a complete carcinogen for the induction of melanoma. By contrast, in humans, the UVR component of sunlight appears to have a much more important role in the aetiology of melanoma. Unlike common melanomas in humans, melanomas in animals generally arise in the dermis and there is negligible epidermal involvement; melanomas in fish may arise from specialized melanocytes not found in humans. Swine melanomas do, however, resemble human melanomas histologically. A strong genetic predisposition for melanoma development such as that seen in perhaps 10% of patients with melanoma can be identified only in fish and swine. In addition, regression, which can be a prominent feature of human melanoma, is seen only in swine.
Experimental animal models that are directly relevant to human melanoma are lacking. We propose the Angora goat as a potentially useful field model with experimental potential and to this end have examined the prevalence and site distribution of all skin cancers in 28 Angora goat herds in Queensland, Australia. The prevalence of benign melanocytic lesions (lentigines) and their experimental induction by sunlight were also investigated. Among 1731 goats over 2 years of age, 139 malignant skin tumors were excised from 95 affected animals. The prevalence of squamous cell carcinoma (SCC) was 3.8% and of melanoma, 2.2%. Main site of occurrence of melanoma (83%) was the dorsal surface of the ear; in contrast SCC occurred mostly (84%) on the perineum. Lentigines were darker and more prevalent on the exposed compared with the unexposed surface of the ear in Angoras, analogous to the higher prevalence of nevi on the exposed compared with the less exposed inner surface of the arm in humans. Lentigines, which were also found on the perineum though lighter in color than on the dorsal ear, were absent in young animals under 3 months but were numerous in 1-3 year olds. Furthermore in an experimental substudy eight goats, having one flank repeatedly shorn and the contralateral flank left unshorn, revealed consistently more solar lentigines on the shorn flank (P < 0.05) when both sides were examined after 9 months. Histopathological examination of paired skin biopsies from five of these goats also showed more abundant pigmentation in skin from the exposed, as compared with the unexposed flank. These findings indicate that sunlight induces tumors and lentigines in goats in a highly site-specific manner. The Angora goat model may suggest paradigms for explaining the site differences observed for human melanoma and may also be useful in the future clarification of molecular changes following carcinogenic levels of sun exposure.
Two groups of 30 dorsally shaved opossums (Monodelphis domestica) were exposed three times per week for 81 weeks to 250 J/m2 of UV radiation from FS40 sunlamps (approximately 150 J/m2 of UV radiation B; UV-B), or to 2.5 x 10(4) J/m2 of UV radiation A (UV-A) from filtered F40BLB fluorescent lamps (black lights). Animals were monitored for the appearance of nonmelanoma skin tumors (NMSTs) and melanocytic hyperplasia (MH). After 81 weeks of exposures, the prevalence of NMSTs was 71% and 4% for animals exposed to UV-B and UV-A, respectively. The difference between the treatment groups was statistically significant (P < 0.001). However, the prevalence of MH in the treatment groups, 31% for UV-B-exposed animals and 22% for UV-A-exposed animals, was not significantly different (P > 0.05). Thus, a dose of UV-A that was relatively ineffective in producing NMSTs, compared to UV-B, was as effective as UV-B in the induction of MH. If, as shown previously, MH is the precursor lesion for melanoma in this model, these results suggest that the action spectra for the induction of melanoma and NMSTs in the opossum are different.
The spontaneous regression of melanoma in Sinclair miniature swine involves the replacement of tumours by pigmented cells, hitherto interpreted as pigment-laden macrophages (PLMs). We hypothesized that these residual cells are terminally differentiated melanoma cells, not monocyte-derived macrophages. Swine melanoma explants with no regression were transplanted into severe combined immunodeficient (SCID) mice. Harvested transplant sites were examined by routine light and electron microscopy techniques. Paraffin sections were also stained with Hoeschst dye and examined by fluorescence microscopy. All but one site had completely regressed and were replaced by PLM-like cells. Hoeschst staining indicated they were of swine, not mouse, origin. The ultrastructural features of the single, partially regressed lesion demonstrated many premelanosomes in these cells. We conclude that tumour differentiation is an important mechanism of regression in the Sinclair swine melanoma model.
Despite the numerous oncogene signaling pathways that have been deciphered, no one is really sure whether drugs designed to target them will cause tumor regression in vivo. Several recently developed animal models of tumor induction provide insight into the prospects for oncogene-specific therapeutics.
Melanoma is the most aggressive of the skin cancers and its prognosis is often poor. The only known environmental risk factor for this tumour is ultraviolet light exposure. This fact together with the existence of melanoma-prone families has prompted investigation of genetic risk factors that may be involved in melanoma development. Inactivation of the INK4a/p16 gene is known to play a role in familial cases. Data on genes or loci involved in sporadic melanoma are less definitive and require more detailed research. In addition to the INK4a locus, other genes involved in melanoma development are discussed here, in particular those genes that participate in the same functional pathway, such as CDK4 and Rb, and p53, which is regulated by the alternative product of INK4a. Evidence showing the possible location of melanoma susceptibility genes on chromosomes 1p, 6, 10q and 11q is analysed along with data showing N-ras, betacatenin, c-myc and MC1R involvement. Melanoma is a well-characterized disease in terms of its progression stages; therefore obtaining precise genetic information is crucial in the development of a stepwise model of melanoma pathogenesis.
Recent advancement in the research of malignant melanoma is reviewed. Among many gene alterations detected in human melanoma, defect of CDKN2A located at chromosome 9p21 seems to be most important in the earlier developmental phase, though significance of this gene in the evolution of melanoma in situ has not been confirmed yet. Deletions of PTEN/MMAC1 on 10q23.3 and AIM1 on 6q21 as well as mutations of ras gene are involved in the later progression stages of melanoma. Adhesion molecules relevant to development and progression of melanoma have been intensely investigated in recent years, revealing crucial roles of cadherins and alpha(v)beta(3) integrin in the biologic behaviors of melanoma cells. Melanoma is characterized by extremely high potential of developing metastases. Dynamic changes of matrix metalloproteinase activity during invasion and movement of melanoma cells may be a major concern in this field. Fragility of blood vessels in melanoma lesions is another important point related to hematogeneous metastases. Acral lentiginous melanoma is a unique subtype of melanoma, because, in contrast to other subtypes, ultraviolet irradiation is not a major factor in its development. Investigation of pathogenesis of acral lentiginous melanoma surely provides us with new information about mechanism of melanocyte transformation. Recent advances in the management of malignant melanoma are also briefly reviewed, such as biochemotherapy, immunotherapy, and gene therapy. Finally, the concept of molecular classification of melanoma by gene expression profile is introduced, which possibly enables us to give the tailor-made therapy for each melanoma patient in the near future.