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Loss of differentiation of 4NQO‐induced rat malignant oral keratinocytes correlates with metastatic dissemination and is associated with a reduced cellular response to TGF‐pi and an altered receptor profile
Author(s) -
Davies Maria,
Paterson Ian C.,
Stone Andrea,
Huntley Susan,
Patel Vyomesh,
Curtis Rory,
Matthews John B.,
Pring Miranda,
Eveson John W.,
Prime Stephen S.
Publication year - 1999
Publication title -
journal of oral pathology and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.887
H-Index - 83
eISSN - 1600-0714
pISSN - 0904-2512
DOI - 10.1111/j.1600-0714.1999.tb02110.x
Subject(s) - receptor , keratinocyte , transforming growth factor , pi , cancer research , pathology , medicine , biology , endocrinology , chemistry , cell culture , genetics , biochemistry
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 5 × 10 6 cells of either cell type at high cell density resulted in approximately 50% of animals forming pulmonary metastases. By contrast, inoculation of 2 × 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‐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 amounts 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 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‐β receptor profile leading to the partial loss of response to exogenous TGF‐β1.