Etude des mécanismes moléculaires impliqués dans le développement des carcinomes spinocellulaires cutanés

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Etude de la voie de signalisation Sonic hedgehog dans les cancers cutanés de patients atteints de Xeroderma pigmentosum

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Effects of XPD Mutations on Ultraviolet-Induced Apoptosis in Relation to Skin Cancer-Proneness in Repair-Deficient Syndromes

To understand the relationship between DNA repair, apoptosis, transcription, and cancer-proneness, we have studied the apoptotic response and the recovery of RNA synthesis following ultraviolet C and ultraviolet B irradiation in nucleotide excision repair deficient diploid fibroblasts from the cancer-prone xeroderma pigmentosum (XP) syndrome patients and the non-cancer-prone trichothiodystrophy (TTD) patients. Analysis of four XPD and four TTD/XPD fibroblast strains presenting different mutations on the XPD gene has shown that XPD cells are more sensitive to ultraviolet-induced apoptosis than TTD/XPD cells, and this response seems to be modulated by the type and the location of the mutation on the XPD gene. Moreover, the other xeroderma pigmentosum fibroblast strains analyzed (groups A and C) are more sensitive to undergo apoptosis after ultraviolet irradiation than normal human fibroblasts, showing that the cancer-proneness of xeroderma pigmentosum patients is not due to a deficiency in the ultraviolet-induced apoptotic response. We have also found that cells from transcription-coupled repair deficient XPA, XPD, TTD/XPD, and Cockayne's syndrome patients undergo apoptosis at lower ultraviolet doses than transcription-coupled repair proficient cells (normal human fibroblasts and XPC), indicating that blockage of RNA polymerase II at unrepaired lesions on the transcribed strand is the trigger. Moreover, XPD and XPA cells are more sensitive to ultraviolet-induced apoptosis than trichothiodystrophy and Cockayne's syndrome fibroblasts, suggesting that both cyclobutane pyrimidine dimers and pyrimidine 6–4 pyrimidone on the transcribed strand trigger apoptosis. Finally, we show that apoptosis is directly proportional to the level of inhibition of transcription, which depends on the density of ultraviolet-induced lesions occurring on transcribed sequences

Abnormal behavior of cultured fibroblasts from nodule and nonaffected aponeurosis of Dupuytren's disease

Vimentin-positive, desmin-negative cells were established in culture from the nodule and from apparently normal palmar aponeurosis of a patient with Dupuytren's disease and compared with normal human embryonic and adult fibroblasts or sarcomatous cells. Cells from the nodule display in vitro biological properties that are intermediate between those expressed by normal fibroblasts and sarcoma cells or cells from the nodule transformed with SV40 virus. Thus, they represent an interesting in vitro model of partially transformed human cells. This behavior is not evolutive and justifies the classification of Dupuytren's disease among the benign mesenchymal tumors. The production of high level of plasminogen activator probably explains the local reactive pathology, and could act as a mitogenic stimulus for the proliferation of the nodule itself. Cultures derived from the apparently normal palmar aponeurosis show some but not all the abnormal growth properties of cells from nodules; this may help to explain the onset of local recurrences. Our results suggest that Dupuytren's disease is not strictly local and limited to the nodules, but affects, at least partially, the whole aponeurosis. Dupuytren's nodules could be considered as a model of tumor progression in a benign situation