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PATHOGENESIS,DIAGNOSIS AND THERAPY OF TUMOUR PROGRESSION IN HUMAN MELANONOMA AND PRECURSOR LESIONS

Objective

The biomedical problems encountered in cancer according to the EC Programme Europe Against Cancer are:

- late and inadequate diagnosis, and
- limited effectiveness of conventional treatment.

In addition there is a lack of insight into the mechanisms of tumour progression.
%Therefore, the strategy to overcome these problems includes:

- detection of markers for UV-induced genetic damage in melanocytic lesions
-improvement of the histopathological diagnosis of cutaneous melanoma and precursor lesions
- identification of the histopathological diagnosis of cutaneous melanoma and precursor lesions
- identification of progression antigens as prognostic markers in primary melanoma and precursor lesions
- diagnosis of early metastases
- identification of the role of cellular adhesion molecules and adhesion receptor molecules in melanoma progression
- development of immune therapy.
Recent research into melanoma progression has yielded interesting findings and promising new approaches to treatment. A Dutch study of human cutaneous melanomas derived from body sites with a high exposure to sunlight showed an N-ras oncogene mutation to be present in 20% of cases studied. It is important to generalise this study to other European countries, as the results will provide information on the frequency of genetic changes that may be involved in the aetiology of the disease. In the area of tumour progression, monoclonal antibodies have been developed that recognise stage specific determinants on melanocytes, called melanoma associated progression antigens. These mainly consist of cellular adhesion molecules or cellular adhesion receptor molecules. Others include the transferrin receptor, the epidermal growth factor (EGT) receptor, and human lymphocyte antigen (HLA) class II antigens. Some of these antigens may contribute to making melanoma cells resistant to the action of immune component cells and the complement system. As for treatment, an area that seems full of promise is immunotherapy. Such approaches include infusing patients with their own expanded and activated lymphokine activated killer (LAK) cells and tumour infiltrating lymphocytes (TIL) together with Interleukin-2 (IL-2), treating with monoclonal antibodies against melanoma associated antigens, and vaccinating with melanoma associated antigens. Of particular interest are the melanoma associated gangliosides. They are immunogenic, and vaccination has been carried out without any adverse effect.

Mortality of melanoma can be lowered either by avoidance or eradication of metastatic disease. Research carried out by the Concerted Action on Melanoma Progression is directed towards the early recognition of neoplastic potential and interference with tumour progression in cutaneous melanocytic lesions.

The research involved has a multidisciplinary approach in the following areas:
(detection of mutations induced by ultraviolet light and the identification of progression genes);
(identification of cellular adhesion molecules and adhesion receptors on human melanoma cells involved in the cellular immune response);
(development of consensus on the diagnosis of early cutaneous melanoma and precursor lesions, detection of progression and regression antigens and prognostic markers);
(development of protocols on therapy and parameters for monitoring the clinical response);
(selection of target molecules, development of protocols).

The Concerted Action creates a European network devoted to biomedical research on melanoma progression. Standardization and quality control of techniques and methods used has already been achieved. Protocols have been developed on early diagnosis and new treatment modalities. A network of reference dermatopathologists has been appointed.
Human cutaneous melanoma has shown a rapidly increasing incidence over the past decade. Despite improved early recognition, it still has a considerable mortality due to metastatic disease. The underlying cause for metastatic disease is tumour progression, which is defined as the acquisition of permanent, irreversible and qualitative changes of characteristics in a neoplasm or its precursor lesion.

It is mandatory that the incidence and mortality of melanoma are lowered. As exposure to UV light may be an important etiologic factor for cutaneous melanoma it is important that markers are identified that are associated with genetic damage to melanocytes. This approach may help to derive an appropriate estimate of the magnitude of UV-irradiation as an etiologic factor in human cutaneous melanoma.
%Mortality of melanoma can be lowered either by avoidance or eradication of metastatic disease. Therefore, the common goal of the Concerted Action on Melanoma Progression is the early recognition of neoplastic potential and interference with tumour progression in cutaneous melanocytic lesions.

Funding Scheme

CON - Coordination of research actions

Coordinator

University Hospital Nijmegen
Address

6500 HB Nijmegen
Netherlands