title: Differentiation of malignant oral rat keratinocytes reflects changes in EGF and TGF-beta receptor expression but not growth factor dependence.
abstract: This study examined the characteristics of keratinocytes from 4-nitroquinoline N-oxide-treated rat oral epithelium that formed well differentiated carcinomas or spindle cell tumours when transplanted s.c. to athymic mice. Small polygonal-type cells in early culture passage gave rise to xenografts that were well differentiated carcinomas with keratin positivity and a differential reactivity with two anti-vimentin antibodies (positive Vim Dako, negative Vim 3B4). Progressive culture of the polygonal cells resulted in cells of a more stellate-like morphology which, when transplanted, formed spindle cell tumours that were keratin negative and vimentin positive (Vim Dako and Vim 3B4). The staining pattern of the xenografts was similar to that of the cultured cell derivatives. By contrast to normal oral keratinocytes which were stimulated by epidermal growth factor (EGF), the parental and xenograft-derived cells were markedly less responsive and at times refractory to EGF. Low affinity EGF receptors characterized normal keratinocytes whilst parental and xenograft-derived cells from well differentiated carcinomas and spindle cell tumours expressed diminished numbers of low and high affinity and high affinity EGF receptors respectively. Normal keratinocytes and parental tumour cells were inhibited by transforming growth factor (TGF-beta) whereas xenograft-derived cell lines from both well differentiated carcinomas and spindle cell tumours were refractory to TGF-beta. TGF-beta receptors were predominantly of high affinity although xenograft-derived cells, particularly from spindle cell tumours, expressed increased numbers of receptors which were of lower affinity. The results indicate that spindle cell tumours are a variant of well differentiated carcinomas and express an aberrant pattern of differentiation. Resistance to EGF-induced stimulation and TGF-beta-induced inhibition appears not to be an integral part of the tumour phenotype but the pattern of EGF and TGF-beta receptor expression closely follows the degree of tumour differentiation.
authors.affiliation: Centre for the Study of Oral Disease, University Department of Oral Medicine, Surgery and Pathology, University of Bristol Dental School, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Game
authors.forename: A
authors.initials: A
authors.lastname: Stone
authors.forename: J B
authors.initials: JB
authors.lastname: Matthews
authors.forename: C
authors.initials: C
authors.lastname: Scully
authors.forename: S S
authors.initials: SS
authors.lastname: Prime
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006133:Growth Substances / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014316:Tritium
chemical_list: D006133:Growth Substances; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014316:Tritium; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D013936:Thymidine