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- 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.
- Authors
Davies, Maria; Paterson, Ian C.; Stone, Andrea; Huntley, Susan; Patel, Vyomesh; Curtis, Rory; Matthews, John B.; Pring, Miranda; Eveson, John W.; Prime, Stephen S.; Davies, M; Paterson, I C; Stone, A; Huntley, S; Patel, V; Curtis, R; Matthews, J B; Pring, M; Eveson, J W; Prime, S S
- 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 tumors (keratin negative and vimentin positive), respectively, in almost 100% of animals at the site of inoculation (floor of mouth). Transplantation of 5×106 cells of either cell type at high cell density resulted, in approximately 50% of animals forming pulmonary metastases. By contrast, inoculation of 2×106 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 to 4 of the undifferentiated spindle cell lines produced comparable levels of TGF-β1. One undifferentiated spindle cell line expressed significantly more TGF-β1 and, following transplantation orthotopically, fewer animals formed pulmonary metastases despite the formation of primary tumours in almost all grafted animals, suggesting that TGF-β1 can act as a tumour suppressor in this cell type. All cell lines produced comparable amount of TGF-β2. The clones of polygonal cells were markedly inhibited and the spindle cells were only partially inhibited by exogenous TGF-β1. Both cell types expressed high-affinity TGF-β cell surface receptors; the ratio of type I to type II TGF-β receptors were 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 counter parts. This may be attributable, in part, to a change in TGF-β receptor profile leading to the partial loss of response to exogenous TGF-β1.
- Subjects
KERATINOCYTES; METASTASIS; TRANSFORMING growth factors; SQUAMOUS cell carcinoma; NUDE mouse; TUMORS
- Publication
Journal of Oral Pathology & Medicine, 1999, Vol 28, Issue 9, p397
- ISSN
0904-2512
- Publication type
journal article
- DOI
10.1111/j.1600-0714.1999.tb02110.x