Clues to epidermal cancer proneness revealed by reconstruction of DNA repair-deficient xeroderma pigmentosum skin in vitro.
Sun exposure has been clearly implicated in premature skin aging and neoplastic development. These features are exacerbated in patients with xeroderma pigmentosum (XP), a hereditary disease, the biochemical hallmark of which is a severe deficiency in the nucleotide excision repair of UV-induced DNA lesions. To develop an organotypic model of DNA repair deficiency, we have cultured several strains of primary XP keratinocytes and XP fibroblasts from skin biopsies of XP patients. XP skin comprising both a full-thickness epidermis and a dermal equivalent was successfully reconstructed in vitro. Satisfactory features of stratification were obtained, but the expression of epidermal differentiation products, such as keratin K10 and loricrin, was delayed and reduced. In addition, the proliferation of XP keratinocytes was more rapid than that of normal keratinocytes. Moreover, increased deposition of cell attachment proteins, alpha-6 and beta-1 integrins, was observed in the basement membrane zone, and beta-1 integrin subunit, the expression of which is normally confined to basal keratinocytes, extended into several suprabasal cell layers. Most strikingly, the in vitro reconstructed XP skin displayed numerous proliferative epidermal invasions within dermal equivalents. Epidermal invasion and higher proliferation rate are reminiscent of early steps of neoplasia. Compared with normal skin, the DNA repair deficiency of in vitro reconstructed XP skin was documented by long-lasting persistence of UVB-induced DNA damage in all epidermal layers, including the basal layer from which carcinoma develops. The availability of in vitro reconstructed XP skin provides opportunities for research in the fields of photoaging, photocarcinogenesis, and tissue therapy.
Bernerd
F
F
L'Oreal, Life Sciences Advanced Research, Centre C. Zviak, 90, Rue du Général Roguet, 92583 Clichy, France.
Asselineau
D
D
Vioux
C
C
Chevallier-Lagente
O
O
Bouadjar
B
B
Sarasin
A
A
Magnaldo
T
T
D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004817:Epidermis / Q000473:pathology; D006801:Humans; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000473:pathology