title: Step-wise progression in human skin carcinogenesis in vitro involves mutational inactivation of p53, rasH oncogene activation and additional chromosome loss.
abstract: Two mechanisms relevant for skin carcinogenesis in man are mutational inactivation of p53 and oncogenic activation of c-rasH gene. Previously, we transfected c-rasH oncogene into human skin keratinocytes (HaCaT) with u.v.-typic mutations in both p53 alleles, which produced benign and malignant tumorigenic clones, expressing similar amounts of mutant Ras protein. Here we show that neither the ras integration site nor the karyotypic changes affects the formation of the benign or malignant tumorigenic phenotype. From the original malignant HaCaT-ras clone we took single human chromosomes, carrying the c-rasH oncogene and transferred them by microcell mediated chromosome transfer into genetically different untransfected nontumorigenic HaCaT cells. This novel approach identified the genetic background of the recipient cell as a critical determinant for the resulting tumor phenotype. Exhibiting similar oncogene expression, microcell hybrids from early passage cells remained nontumorigenic or formed benign tumors, while those with more cytogenetic aberrations (later passages) and loss of > 1 copy of chromosome 15 became malignant. Since aberrations in chromosome 15 were also detected in three of five human skin carcinoma lines this study provides evidence that p53 and c-rasH mutations are early events of human skin carcinogenesis, while loss of gene(s) on chromosome 15 is a late event.
authors.affiliation: Division of Carcinogenesis and Differentiation, German Cancer Research Center, Heidelberg.
authors.forename: P
authors.initials: P
authors.lastname: Boukamp
authors.forename: W
authors.initials: W
authors.lastname: Peter
authors.forename: U
authors.initials: U
authors.lastname: Pascheberg
authors.forename: S
authors.initials: S
authors.lastname: Altmeier
authors.forename: C
authors.initials: C
authors.lastname: Fasching
authors.forename: E J
authors.initials: EJ
authors.lastname: Stanbridge
authors.forename: N E
authors.initials: NE
authors.lastname: Fusenig
mesh_terms: D002460:Cell Line; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12; D002894:Chromosomes, Human, Pair 4; D018014:Gene Transfer Techniques; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics