ScienceWeek

5. SKIN CANCER

MALIGNANT MELANOMA: AN UPDATE

A. Slominski et al (University of Tennessee, US) discuss recent research on malignant melanoma, the authors making the following points:

1) Melanoma is not genetically homogeneous, and the existing differences between pathologic categories, particularly in areas such as type of growth phase (radial vs. vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications.

2) Chromosomal aberrations and gene mutations are found in both sporadic and familial melanomas. Among the most important are those affecting the 9p21 gene, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior of the malignancy.

3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen.

4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly becoming of significance in the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.

Arch. Pathol. Lab. Med. 2001 125:1295

J. Am. Med. Assoc. 2002 287:172

Related Background:

ON CHILDHOOD SUNBURN AND ADULT MELANOMA

F.P. Noonan et al (George Washington University, US) discuss early sunburn and adult melanoma. Retrospective epidemiological data have indicated that cutaneous malignant melanoma may arise as a consequence of intense and intermittent exposure of the skin to ultraviolet radiation, particularly in children, rather than from cumulative lifetime exposure associated with other forms of skin cancer. The authors report the use of a genetically engineered mouse model to demonstrate that a single dose of burning ultraviolet radiation in neonates, but not adults, is necessary and sufficient to induce tumors with high penetrance that are reminiscent of human melanoma. The authors suggest their results provide experimental support for epidemiological evidence that childhood sunburn poses a significant risk for development of this potentially fatal disease. Concerning the question of why neonatal mouse skin is so sensitive to ultraviolet-induced melanogenesis, the authors point out that since melanocyte-precursor cells are more abundant in neonatal than in adult skin and more proliferative under stress, ultraviolet light exposure may stimulate proliferation of DNA-damaged neonatal progenitors and thus facilitate melanogenesis. Also, early exposure to intense ultraviolet radiation might affect the developing immune system, promoting future tolerance to arising melanoma. However, the authors also suggest that caution is called for in extrapolating these results to sunburn in children. The difference in thickness between mouse and human skin could affect the penetration of ultraviolet radiation. Moreover, the human age equivalent to a 3.5-day-old neonatal mouse cannot be precisely calculated.

Nature 2001 413:271

Related Background:

MEDICAL BIOLOGY: PATHOGENESIS OF UV INDUCTION OF MELANOMAS

Skin cancers, predominantly *basal-cell and *squamous-cell *carcinomas, have accounted for an estimated 40 percent of all cancers in the US in recent years, and the frequency of these cancers has been increasing. The most common fatal skin cancer is *melanoma, and this has also increased, indeed by a factor of approximately 15 in the past 60 years. In 1997, more than 40,000 new cases of melanoma were diagnosed in the US, with more than 7200 fatalities.

B.A. Gilchrest et al (Boston University, US) present an extensive review of current research concerning the pathogenesis of melanoma induced by UV radiation, the authors making the following points:

1) The factors underlying the rapid increase in the incidence of skin cancer are incompletely understood, but increased total exposure to the Sun, and in the case of melanoma, altered patterns of exposure, are strongly implicated.

2) The risk of melanoma is higher in fair-skinned people, especially those with blond or red hair who sunburn and freckle easily, than in people with darker complexions. The incidence of melanoma among whites is inversely related to the latitude of residence, with the world's highest incidence in Australia, a subtropical country with a largely Celtic population. Conversely, melanomas are uncommon in darker-skinned people.

3) The epidemiologic evidence implicating solar exposure in the causation of melanoma is supported by biologic evidence that damage caused by ultraviolet radiation, particularly damage to DNA, plays a central part in the pathogenesis of these tumors.

4) Age plays a major part in vulnerability to photocarcinogenesis. Aging (the passage of time) provides more opportunities for the initiation of tumor formation (the induction of mutations by exposure to UV radiation) and for the promotion of tumor formation (the reparative cell proliferation after exposure to UV radiation or after other skin injury). There is an age-associated decrease in the capacity to repair DNA, and a consequent increase in the rate of mutations of DNA. Moreover, the rate of removal of UV-radiation-induced DNA photoproducts from UV-irradiated skin decreases with age, especially during the first two decades of life.

5) There has been considerable research addressing the relative contributions of UV-B wavelengths (290-320 nm) and UV-A wavelengths (320-400 nm) to photocarcinogenesis, particularly to the development of melanoma. UV-B radiation is overwhelmingly responsible for the formation of the principle DNA lesions, cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts, whose incorrect repair leads to mutations. However, UV-A radiation is far more abundant in sunlight than UV-B radiation, and UV-A radiation causes oxidative DNA damage that is also potentially mutagenic. UV-A radiation is also believed to contribute substantially to immunosuppression, thus preventing immunologic rejection of nascent UV-induced skin cancers.

6) Unlike the more common skin cancers, which are associated with total cumulative exposure to UV radiation, melanomas are associated with intense intermittent exposure. Thus, basal-cell and squamous-cell carcinomas occur most commonly in maximally solar-exposed areas of the body (e.g., face, back of hands, forearms, and in persons with almost daily and substantial lifetime exposure to UV radiation, such as farmers and sailors). In contrast, melanoma occurs most commonly in areas of the body exposed to the Sun intermittently, such as the back in men and the lower legs in women, with relative sparing of more frequently exposed sites such as the face, hands, and forearms. Melanoma is most common in persons with predominantly indoor occupations whose exposure to the Sun is limited to weekends and vacations. Indeed the large increase in the incidence of melanoma in recent decades has been attributed in part to the ability of large numbers of people to travel long distances to obtain intense exposure to the Sun in winter.

7) The authors propose a hypothesis to explain the epidemiology of melanoma as compared with non-melanoma skin cancer, the authors suggesting that the data predict that a high-dose first exposure to the Sun after a prolonged period of Sun avoidance will cause substantial damage to DNA in *melanocytes and *keratinocytes, both of which at that time have a relatively low base-line capacity for DNA repair and a low melanin content. The authors propose that the final effect of UV radiation is not attributable simply to the cumulative dose -- the arithmetic sum of all individual exposures over a lifetime -- but rather may be strongly influenced by the dose per exposure and by the pattern of exposures.

8) The authors conclude: "Protection from the Sun is critical to the prevention of both melanoma and non-melanoma skin cancers, and protection is most effective when it is begun in early childhood. It is especially important to protect against intermittent Sun exposures, in order to reduce genomic damage at a time of maximal cellular vulnerability and to reduce the risk of melanoma."

New Engl. J. Med. 1999 340:1341

Notes:

*basal-cell: A basal cell is a cell of the deepest layer of stratified epithelium. In animals, including humans, epithelial cells (epithelium) compose the cell layers that form the interface between a tissue and the external environment, for example, the cells of the skin, the lining of the intestinal tract, and the lung airway passages. The term "stratified epithelium" is a general term for epithelium composed of several layers of different cell types.

*squamous-cell: The cells of the epithelium are for the most part closely packed cells with little extracellular material between adjacent cells, the cells arranged in continuous sheets in either single or multiple layers. The cells may be flat, cube-like, columnar, or a combination of shapes, and "squamous" cells are flattened and scale-like.

*carcinomas: In general, a carcinoma is any malignancy derived from epithelial tissue.

*melanoma: Melanomas are a group of skin cancers involving *melanocytes, cells found throughout the lower layers of the skin.

*melanocytes: (melanodendrocytes) Pigment-producing cells located in the deepest (basal) layer of the skin (epidermis) with branching processes by means of which melanin-containing bodies (melanosomes) are transferred to epidermal cells with a resultant pigmentation of the epidermis.

*keratinocytes: "Keratinocyte" is a generic term for any mammalian epithelial cell that produces keratin, a group of proteins present in cuticular structures (e.g., hair, nails).

Related Background:

ALARM AT INCREASED INCIDENCE OF MELANOMA CANCERS

Melanocytes, cells which synthesize inclusions of the dark pigment melanin, are found in the skin, choroid of the eye, and hair. Melanocyte cancers are called melanomas, and if they are of the rapidly proliferating type, and not caught early, they have a high fatality rate. At the present time, the incidence of melanoma in the U.S. is increasing faster than any other cancer, and the statistics seem incredible: 0.0007 in 1935, 0.004 in 1977, 0.01 in 1997. According to projections, in the U.S. this year, 40,300 new cases will be diagnosed, and 7,300 people will die from the disease. The majority of oncologists and epidemiologists believe this striking increase in incidence is real and not a function of ambiguous diagnostic techniques. They point to the simple fact that deaths from melanoma have increased along with the incidence, even though early diagnosis and improved treatment methods have increased the 5-year survival rate. The projected U.S. incidence of melanoma in the year 2000 is 0.013, which means at that time 1 in 75 people will expect to be diagnosed with the disease.

New York Times 6 Aug 1997

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