Zusammenfassung
Epitheliale Tumoren der Haut, d. h. Basalzellkarzinome und Plattenepithelkarzinome, sind die häufigsten Tumorerkrankungen des Menschen und zeigen eine stetig steigende Inzidenz. Das Verständnis der für die Entstehung dieser Tumoren verantwortlichen genetischen Veränderungen ist von entscheidender Bedeutung für die Entwicklung neuer pathogeneseorientierter Therapien. Basalzellkarzinome sind durch eine generelle Aktivierung des Sonic-Hedgehog- (SHH-)Signalweges charakterisiert, die in der Mehrzahl der Tumoren durch Mutationen in den Genen PTCH und SMOH hervorgerufen wird. Zusätzlich finden sich in etwa der Hälfte der Fälle zumeist UV-typische Mutationen im Tumorsuppressorgen TP53. Plattenepithelkarzinome zeigen keine PTCH- oder SMOH-Mutationen, wohingegen TP53-Mutationen nahezu immer nachweisbar sind. Zusätzlich finden sich oftmals Veränderungen in Zellzyklus-regulierenden Genen, darunter besonders oft eine Inaktivierung des Tumorsuppressorgens CDKN2A. Spezifische Inhibitoren des SHH-Signalweges zur Behandlung des Basalzellkarzinoms befinden sich zurzeit noch im experimentellen Stadium. Die lokale Immuntherapie epithelialer Tumoren stellt ein weiteres pathogeneseorientiertes Therapiekonzept dar, das eine gegen den Tumor gerichtete zelluläre Immunantwort stimuliert, aber auch direkt apoptotische Signale in den Tumorzellen induziert.
Abstract
Basal cell carcinomas and squamous cell carcinomas are the most common human cancers and increasing in incidence. The development of novel, pathogenesis-based therapies requires a better knowledge of the molecular mechanisms leading to the development of these tumors. Basal cell carcinomas are characterized by aberrant activation of Sonic-Hedgehog (SHH) signaling due to mutations in the PTCH or SMOH genes. In addition, about 50% of the cases carry mutations in the TP53 tumor suppressor gene. Squamous cell carcinomas lack alterations of SHH signaling, while TP53 mutations are detectable in virtually all cases. Alterations in cell cycle regulatory genes, such as CDKN2A, are also common. Recently, specific inhibitors of the SHH-signaling pathway have been developed and shown promising results in preclinical studies on experimental basal cell carcinomas. However, the clinical significance of such targeted molecular therapy remains to be evaluated. Another successful pathogenesis-based therapy, which is already in clinical use, is the administration of topic immune response modifier imiquimod. This drug can eradicate non-melanoma skin cancers by different mechanisms, including cytokine-mediated stimulation of the anti-tumor immune response, as well as the induction of tumor cell apoptosis.
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Reifenberger, J., Schön, M.P. Molekulare Grundlagen und pathogeneseorientierte Therapie epithelialer Tumoren der Haut. Hautarzt 54, 1164–1170 (2003). https://doi.org/10.1007/s00105-003-0631-1
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DOI: https://doi.org/10.1007/s00105-003-0631-1
Schlüsselwörter
- Basalzellkarzinom
- Plattenepithelkarzinom
- Molekulare Pathogenese
- Mutation
- Pathogeneseorientierte Therapie