Sci. Aging Knowl. Environ., 24 May 2006
Vol. 2006, Issue 9, p. pe13
[DOI: 10.1126/sageke.2006.9.pe13]

PERSPECTIVES

The Age of Skin Cancers

Anu Desai, Richard Krathen, Ida Orengo, and Estela E. Medrano

The authors are in the Department of Dermatology (A.D., R.K., I.O., E.E.M), the Department of Molecular and Cellular Biology (E.E.M.), and the Huffington Center on Aging (E.E.M.) at Baylor College of Medicine, Houston, TX 77030, USA. E-mail: medrano{at}bcm.tmc.edu

http://sageke.sciencemag.org/cgi/content/full/2006/9/pe13

Key Words: skin cancers • melanoma • nevi • senescence

Introduction

Aging is the single most important risk factor in the development of human cancers [reviewed in (1) and see "Dangerous Liaisons"], and skin cancers are no exception. The incidence of these tumors rises sharply in the later decades of life, and the three most common types of skin cancer, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, account for almost half of all cancer diagnoses with more than 1 million new cases each year (2). Intriguingly, melanomas stand out from BCCs and SCCs in that, in addition to aging, gender is also a risk factor (3, 4).

The marked correlation between skin cancer and aging is likely a result of the interplay of a number of factors, including (i) cumulative exposure to ultraviolet (UV) radiation, (ii) decreased ability to repair DNA, and (iii) decreased immune function (5, 6). It is currently accepted that the carcinogen most strongly correlated with skin cancers is UV radiation. The fact that a cell survives innumerable insults to its DNA attests to the proficiency of the repair enzymes in dealing with threats. However, with age these repair enzymes face a functional decline (7). The ability to remove UV-induced DNA dimers has been shown to decrease approximately 0.6% per year from the first to the tenth decade of life, with a corresponding increase in DNA mutability (8). Even with DNA mutations accumulating, the cell may be able to avoid malignant transformation if intact p53 and/or retinoblastoma (RB) systems direct it to apoptosis or senescence. In fact, senescence functions in vivo as a potent tumor suppressor mechanism in melanocytes and other cell types (9-12) (see Sage Perspective). In melanocytes, activating mutations in the kinase B-RAF, a downstream effector of the oncogene RAS, trigger proliferation and the formation of nevi (moles), which are believed to develop from a single mutant melanocyte (12). However, further proliferation and risk of acquiring additional mutations is curtailed by the activation of the RB/p16INK4a pathway (see figure 1 in Sharpless Perspective), which results in irreversible growth arrest and senescence. It is easy then to understand why alterations in the p53 and RB pathways set the stage for carcinogenesis.

Aging correlates with decreased immune function, which in turn may favor the emergence of skin cancers. Skin-specific immune cells, such as Langerhans cells, show a decrease in number as well as antigen-presenting function with age (13, 14). Changes also occur in T cells, including (i) a decrease in the proliferative response, (ii) decreased cytolytic activity, and (iii) a decreased repertoire of T cell antigen receptors (15) (see Koch Perspective and "Immunity Challenge"). These changes adversely affect the ability of the immune system to detect and destroy skin cancers

Basal Cell Carcinoma

BCCs account for approximately 75% of skin cancer diagnoses and are the most common cancer overall in fair-skinned populations (6). They typically appear de novo on sun-exposed skin. Metastasis is exceedingly rare, but local invasion can cause significant morbidity, particularly in the head and neck. The predominant mutations associated with BCCs are mutations in the mitogenic sonic hedgehog signaling pathway, which also plays an important role in embryonic development, with more than 70% of sporadic cancers having a mutation in this pathway (6).

Squamous Cell Carcinoma

SCCs are the second most common type of skin cancer and typically present on chronically sun-damaged skin. Like BCCs, SCCs can cause substantial local destruction. However, SCCs are much more prone to metastasis than BCCs, especially when found on the high risk areas of the ears, lips, and genitals. Furthermore, SCCs arise from precursor lesions known as actinic keratoses (6). Genetic studies on SCC have not been as conclusive as for BCC, but evidence does point to a prominent role for p53 mutations (16). Apoptosis is also inhibited in chronically UV-damaged cells, possibly through reduced action of Fas ligand, a member of the tumor necrosis factor family that can induce apoptosis upon binding to a target cell (17, 18). Thus, the damage to p53 seen in the majority of SCCs may not be directly oncogenic but may instead set the stage for cells to pick up other mutations. Indeed, mutations in the ras pathway seem to correlate with SCC, particularly UV-signature mutations at codon 12 of the K-ras gene and codons 12, 13, and 61 of H-ras (19).

Melanoma

Melanoma is the most deadly of the skin cancers. On the basis of the most recent data from the American Cancer Society, it is estimated that 59,580 new cases were diagnosed in 2005 with 7,700 deaths related to the disease. The median age at diagnosis for melanoma of the skin for the years 1998 to 2002 was 57 years of age (SEER Cancer Statistics).

Melanocytes are the cell type from which melanoma arises. Melanocytes are specialized cells that synthesize and transfer the pigment melanin to surrounding keratinocytes, leading to skin pigmentation and protection against solar exposure. The skin of older Caucasian individuals frequently becomes mottled as a result of dysfunction of the melanin-forming pathway. In vitro, normal senescent human melanocytes show a dramatic reduction in the levels of MITF (microphthalmia-associated transcription factor) (20), a critical transcription factor involved in the commitment, proliferation, and survival of melanocytes before and/or during their migration from the neural crest [reviewed in (21, 22)]. In addition, dopachrome tautomerase, a crucial enzyme in the melanin pathway, is also down-regulated in senescent melanocytes (20). As a consequence of such alterations, senescent melanocytes may display altered melanin chemistry and, consequently, increased susceptibility to DNA damage.

In humans, the number of active melanocytes, measured by the dihydroxyphenylalanine reaction, which detects the catalytic activity of tyrosinase in the melanin synthesis pathway, was shown to decrease significantly with age in all 17 body sites studied (23). In contrast, aging increases the incidence of benign and malignant melanocyte lesions. Solar lentigines ("aging spots") are common benign pigmented lesions that appear with higher frequency in the skin of older as compared with younger Caucasian individuals (Fig. 1). In turn, the incidence of lentigo maligna, a pre-invasive melanoma induced by chronic sun exposure, primarily increases in older populations.


Figure 1
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Fig. 1. Uneven skin pigmentation and pigmented lesions are hallmarks of old Caucasian skin.

 
Melanoma is a very complex cancer resulting from genetic, environmental, and unknown host factors. Genesis of these tumors is associated with a number of melanoma-relevant oncogenes, aberrant signal transduction pathways, and alterations in the melanoma cell cycle (24-26). In addition, alterations in the interactions between the melanoma and its microenvironment may be essential for tumor progression (27). Prolonged exposure to sunlight and sunburn during childhood and intense, intermittent sun exposure in adulthood are major risk factors for melanoma. A comparison of genome-wide alterations in the mutational status of B-RAF and N-RAS in individuals with different degrees of sun exposure (28) identified a distinct pattern of genomic mutations and frequency of B-RAF and N-RAS mutations (29).

Puzzling new data show that the incidence of melanoma is rapidly rising in older men (Fig. 2). More important, males aged 60 years or older show statistically significant increased rates for thick melanoma tumors (≥4 mm) (3) (which have poor prognosis) as compared to the rates for women of the same age or men under 40 years. These results are counterintuitive, as one would have predicted a higher incidence in females resulting from increased sun exposure habits and the common use of tanning beds. So, why is the incidence of melanoma increasing in older men as compared with older women? There are no clear answers, but it is worth discussing some possible reasons. The most straightforward one would be that men have more sun exposure related to recreational outdoor activities and/or occupations than women. But in biology nothing is simple, so more than one factor may be responsible for such increased risk. In fact, the increase in the frequency of melanoma is higher in areas with less ambient UV flux (4). Hormones could also play a role, because androgens can prolong skin inflammation and reduce the rate of wound healing (30), two important factors in carcinogenesis. Whether related to male hormones or to yet-to-be-defined intrinsic factors, men under 50 years of age have statistically higher melanocyte counts than women in both sun-exposed and non-sun-exposed areas, a trend that continues in older men (23). So, can more epidermal melanocytes increase the incidence of melanoma in men? Also to be considered are epigenetic modifications (such as changes in the structure of chromatin; see Vaquero Review), because they can alter cellular differentiation and consequently drive tumor development (31). For example, person-to-person variations in the epigenetic silencing of IGF2 (insulin-like growth factor 2) are related to the predisposition to colon cancer [reviewed in (32)].


Figure 2
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Fig. 2. Data from the Surveillance Epidemiology and End Results (SEER) program, National Cancer Institute. SEER Age Adjusted Incidence Rates by Race and Sex for Melanoma of the Skin, Registries for 1973 to 2002. Age-Adjusted to the 2000 U.S. Standard Population.

 
In sum, the above data indicate that it is essential to determine the molecular reasons by which the incidence of melanoma is increasing specifically in older men. Equally important will be to increase the awareness that the geriatric male patient belongs to a high-risk population for melanoma skin cancer (33).


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Citation: A. Desai, R. Krathen, I. Orengo, E. E. Medrano, The Age of Skin Cancers. Sci. Aging Knowl. Environ. 2006 (9), pe13 (2006).




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