[Frontiers in Bioscience 3, d1005-1010, September 15, 1998]

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Friedegund Meier1, Kapaettu Satyamoorthy1, Mark Nesbit1, Mei-Yu Hsu1, Birgit Schittek2, Claus Garbe2, and Meenhard Herlyn1

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 191041, Department of Dermatology, University of Tuebingen, Liebermeisterstr.25, 72076 Tuebingen, Germany2

Received 7/17/98 Accepted 8/10/98


Figure 1 depicts the five steps of melanoma development and progression (2). A recent refinement divides lesions into three classes: class I represents "precursor" nevi; class II lesions are "intermediates" with melanocytic cells confined to the epidermis or with microinvasion into the dermis and represented by in situ and invasive RGP melanomas; and class III are VGP tumorigenic melanomas (3). As in any neoplastic system, individual melanomas can skip steps in their development, appearing without identifiable intermediate lesions. Alternatively, melanoma can arise from malignant transformation of precursor cells.

Figure 1. Melanoma development and progression. The model, developed by Clark, Elder, and Guerry (2), implies that melanoma commonly develops and progresses in a sequence of steps from nevic lesions which can be histologically identified in approximately 35% of cases. However, melanoma may also develop directly from normal cells. The role of melanoblasts (immature melanocytes) in melanogenesis remain poorly defined. Cells from lesions persist, but non-tumorigenic lesions tend to disappear through apoptotic or differentiation pathways as yet undefined.

Figure 2 summarizes the genetic and biological events leading to melanoma development and progression. The dynamic progression from a resting melanocyte to a common acquired nevus is very common and does not appear to accompany genetic changes. Nevus cells isolated from common acquired nevi have a finite life span and generally do not carry cytogenetic abnormalities (4-6). We postulate that melanocytes progress to a nevus by escaping from the normal contact-mediated controls of keratinocytes, the dominant cellular partner of melanocytes in the epidermis and able to control the growth, morphology, and antigenic phenotype of melanocytes (7, 8) by establishing direct contact through the cell-cell adhesion receptor E-cadherin. This contact, in turn, facilitates formation of gap junctions through connexin 43 (9). It remains unclear whether signals for phenotypic control over melanocytes are relayed through E-cadherin, gap junctions or other accessory mechanisms. Nevertheless, E-cadherin downregulation coincides with melanoma progression. Reduced E-cadherin expression can be observed early in the nevus stage, and the majority of melanomas are E-cadherin-negative (10). In contrast, expression of N-cadherin is upregulated in nevi and melanomas. Such a shift in cadherin profile confers new adhesive properties to the cells. Acquisition of N-cadherin may allow gap junctional communication of nevus and melanoma cells with N-cadherin-expressing fibroblasts and endothelial cells (unpublished data). Genetic changes are anticipated when dysplastic nevi develop, but the nature of these changes is currently unknown. It is possible that mechanisms leading to persistence and proliferation of dysplastic nevi rest in the dysfunction of the physiological cascade of apoptosis. Thus, the cell cycle checkpoint pathways (including p53 and myc) may be involved in the development of melanocytic dysplasia (2). Progression from dysplasia to RGP primary melanoma is gradual and spontaneous, and may not require additional molecular changes.

Figure 2. Genetic and biological events leading to tumor progression in the human melanocytic system. The progression from normal melanocyte to nevus may be initiated by loss of contact between melanocytes and keratinocytes, i.e., the melanocytes escape from keratinocyte (KC) control. Genetic changes, which are currently not defined, are expected at the transition from common acquired (benign) nevus to dysplastic nevus/RGP/in situ melanoma (left vertical arrow), allowing cells to persist. Additional genetic changes are expected in the progression from RGP/in situ melanoma to VGP (right vertical arrow). At the VGP (tumorigenic) step, increased growth and stroma induction occurs.

The transition from RGP to VGP is a biologically and clinically critical step, accompanying additional genetic abnormalities. However, the specifics are largely unknown. In sections of lesions and in cultured cells, we have described a variety of changes at the biological level which explain RGP-VGP progression (11, 12). Table 1 summarizes the biological differences between RGP and VGP melanoma cells. Unlike RGP melanomas, VGP cells are metastasis-competent (13) and are easily adapted to growth in culture. In addition, VGP cells are less dependent on exogenous growth factors (14) and have growth characteristics similar to metastatic cells, such as anchorage-independent growth in soft agar and tumorigenesis in immunodeficient mice. VGP primary melanomas display numerous cytogenetic abnormalities, suggesting considerable genomic instability. No major additional genetic changes may be required for further progression to metastatic dissemination since most VGP melanomas can be readily adapted to a metastatic phenotype through selection in growth factor-free medium or induction of invasion through artificial basement membranes (15). This suggests that micro-environmental factors such as cell-matrix and cell-cell signaling are critical for the metastatic phenotype.

Table 1. Biological differences between RGP and VGP melanoma cells




Metastatic competence in patients



Growth in vitro



Growth factor dependence


only IGF-I

Stimulation by TPA





Growth in soft agar




no survival or slow growth