The third most frequent cancer of the skin, melanoma, is derived from melanocytes. These cells belong to a distinct cell lineage as keratinocytes. During development, melanocyte precursors migrate from the neural crest to the basal layer of the skin. Melanocytes specialize in synthesizing the pigment melanin from tyrosine. The enzymes of melanin biosynthesis, such as tyrosinase, are only expressed in this cell type. The insoluble pigment is transported by dendritic processes to surrounding epidermal keratinocytes and deposited in them. Differentiating keratinocytes transport melanin to the upper layers of the skin where it absorbs visible and UV light, protecting the living cells of the skin.

Skin pigmentation in man is highly variable. It ranges from a complete lack due to mutations in tyrosinase ('albino') to very intense, e.g. in populations from equatorial Africa. In most humans, pigmentation is inducible in response to sun exposure. It is regulated by interaction of melanocytes with the neighboring keratinocytes and by the hormone aMSH (melanocyte stimulating hormone).

The hormone acts specifically on melanocytes because they express the MC1R receptor (Figure 12.6). This is a classical 'serpentine' receptor coupled to trimeric Gs proteins that activate adenylate cyclase. As in all cell types, increased cAMP activates protein kinase A which induces transcription through the CREB transcription factor. Specifically in melanocytes, CREB induces another transcriptional activator, MTF, which is actually responsible for the induction of melanocyte-specific genes and increased production of melanin. In normal melanocytes proliferation is also dependent on aMSH.

The differences in pigmentation and its inducibility are categorized as 'skin types' by dermatologists. For instance, persons with skin type I have low pigmentation and very little inducibility, whereas persons with skin type II have also relatively pale skins, but develop some pigmentation in response to sun-light. Skin type I is prevalent in Northern and Northwestern European populations, presumably as an evolutionary adaptation to less intense sun exposure. Therefore, travel and migration of Northern European to areas with intense sun exposure is a major factor in the alarming rise of skin cancer incidence in these countries and in states like Australia with a high proportion of immigrants from Northern Europe. Skin types are mostly caused by polymorphisms in the aMSH receptor MC1R. MC1R is thus a cancer predisposition gene (^Table 2.4).

Melanoma is a much more lethal cancer than BCC and SCC, because of its stronger invasive and metastatic potential. However, many genetic alterations in this cancer are not too different from those in SCC, in particular (Table 12.1). Frequent chromosomal losses affect chromosomes 9p and 17p and contribute to inactivation of CDKN2A and TP53. The second alleles of these genes are subject to point mutations. These carry occasionally the signature of UVB carcinogenesis, but not as regularly as in BCC and SCC. In many cases, CDKN2A is inactivated by homozygous deletions which obliterate expression of p14ARF1 in addition to that of p16INK4A and in many cases p15INK4B as well. The overall effect of these changes would be loss of function of the TP53 and RB1 regulatory systems contributing to immortalization, loss of cell cycle control, and genomic instability.

Figure 12.6 Mechanisms of aMSH action C and R: catalytic and regulatory subunits of protein kinase A (PKA). See text for further explanation.

In melanoma, loss of p16INK4A function may be particularly important. In some of the families prone to melanoma development, germ-line mutations in CDKN2A were found which inactivate p 16INK4A or at least diminish its function as an inhibitor of CDK4 in biochemical assays. In fact, in a few families with predisposition to melanoma, mutations were detected in CDK4, always affecting the part of the kinase to which the p16INK4A inhibitor binds. Of note, in melanoma-prone families, an association between UV exposure and cancer development is maintained. So, this may be regarded as a border-line case between high-risk gene mutations and mutations modulating the sensitivity to exogenous agents (cf. 2.3).

Germ-line mutations in CDKN2A have also been observed in patients with pancreatic cancers, and melanomas, too, have occurred in these families. However, germ-line mutations in CDKN2A do not lead to a severe generalized cancer syndrome such as the Li-Fraumeni-syndrome caused by TP53 mutations. This is certainly unexpected in view of the frequent inactivation of the locus in a wide range of human cancers (^6.4).

Further chromosomal losses in melanoma affect chromosomes 3p, 6q, and 10q. At 10q, the PTEN gene is likely involved, and as in many other human cancers, this may an important step during progression (^6.3).

A further set of alterations in melanoma activate the canonical MAPK pathway. Activating mutations in the NRAS gene occur in a subset of melanomas. In a complementary fashion, the BRAF gene harbors mutations that lead to an increased activity of the protein kinase. There are multiple pathways emerging from RAS and three different RAF genes and proteins in humans (^6.2). The complementarity of these mutations indicates that the MAPK pathway is particularly important in tumor formation by activated RAS and that BRAF, among the three protein kinases, is the one transducing the most relevant signals. However, since this constellation has, so far, been found in a restricted number of cancers, it could reflect a cell-type specific 'wiring' of the MAPK signaling network.

There is also some evidence for altered responses to melanocyte-specific growth factors like aMSH in melanoma.

Finally, the most pressing question is of course, what makes melanoma so much more invasive than SCC and BCC?13 Several points are discussed in this regard. (1) Melanocytes are ontogenetically derived from a highly mobile and migratory cell type. So, they may easily fall back into a 'fetal' pattern of behavior. (2) Melanocytes are very peculiarly located. They sit as single cells at the basis of the epithelium and while they maintain cell-cell-contacts with keratinocytes, these are flexible and certainly not comparable to the multiple junctions between proper epithelial cells (^■9.1). So, it may be less complicated for them to dissociate from the epithelium and grow or migrate into the dermis. (3) There are more molecular changes in melanoma typically associated with invasion and metastasis. Melanoma appear to express higher levels of certain metalloproteinases (^9.3), they exhibit more consistently down-regulation of responsiveness to TGFp (^6.7), and they express chemokine and cytokine receptors that may allow 'homing' to certain metastatic sites (^9.6).

13 One might, of course, argue that cancers arising in the interior of the body could be no more aggressive than SCC and BCC, but simply become detected much later. This may indeed be so in some cases. However, very "big" BCC in particular do not metastasize, whereas relatively small melanomas can give rise to metastases, although the risk is clearly related to their size and particular to their depth of growth.

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How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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