title: Loss of differentiation of 4NQO-induced rat malignant oral keratinocytes correlates with metastatic dissemination and is associated with a reduced cellular response to TGF-beta1 and an altered receptor profile.
abstract: This study examined the metastatic capacity of clonal populations of 4NQO-induced rat malignant oral keratinocytes following orthotopic transplantation to athymic mice. Polygonal and spindle cells formed well-differentiated squamous cell carcinomas (keratin positive and vimentin negative) and undifferentiated spindle cell tumours (keratin negative and vimentin positive), respectively, in almost 100% of animals at the site of inoculation (floor of mouth). Transplantation of 5x 10(6) cells of either cell type at high cell density resulted in approximately 50% of animals forming pulmonary metastases. By contrast, inoculation of 2x 10(6) differentiated polygonal cells resulted in the formation of significantly fewer pulmonary metastases than the undifferentiated spindle cells. A single well-differentiated clone of polygonal cells and 3 of 4 of the undifferentiated spindle cell lines produced comparable levels of TGF-beta1. One undifferentiated spindle cell line expressed significantly more TGF-beta1 and, following transplantation orthotopically, fewer animals formed pulmonary metastases despite the formation of primary tumours in almost all grafted animals, suggesting that TGF-beta1 can act as a tumour suppressor in this cell type. All cell lines produced comparable amounts of TGF-beta2. The clones of polygonal cells were markedly inhibited and the spindle cells were only partially inhibited by exogenous TGF-beta1. Both cell types expressed high-affinity TGF-beta cell surface receptors; the ratio of type I to type II TGF-beta receptors was 1.0:<3.0 in the spindle cells and 1.0:17.9 in the polygonal clone. The results suggest that differentiated rat malignant oral keratinocytes are less aggressive and have a decreased potential to metastasise than their undifferentiated spindle cell counterparts. This may be attributable, in part, to a change in TGF-beta receptor profile leading to the partial loss of response to exogenous TGF-beta1.
authors.affiliation: Department of Oral and Dental Science, University of Bristol, UK.
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: I C
authors.initials: IC
authors.lastname: Paterson
authors.forename: A
authors.initials: A
authors.lastname: Stone
authors.forename: S
authors.initials: S
authors.lastname: Huntley
authors.forename: V
authors.initials: V
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Curtis
authors.forename: J B
authors.initials: JB
authors.lastname: Matthews
authors.forename: M
authors.initials: M
authors.lastname: Pring
authors.forename: J W
authors.initials: JW
authors.lastname: Eveson
authors.forename: S S
authors.initials: SS
authors.lastname: Prime
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D002277:Carcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D002454:Cell Differentiation; D017690:Cell Transplantation; D002999:Clone Cells; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000556:secondary*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D015112:4-Nitroquinoline-1-oxide