Loss of expression of TGF-beta1, TbetaRI, and TbetaRII correlates with differentiation in human oral squamous cell carcinomas.

Despite advances in biological and molecular characteristics, the prognosis of oral squamous cell carcinomas is still very unfavourable and is based on the classical clinicopathological parameters. However, tumors with similar clinicopathological characteristics may differ dramatically in their clinical outcome. Thus, the identification of novel prognostic factors is necessary to improve prognostic and therapeutic approaches. Transforming growth factor-ß1 (TGF-ß1) is a potent growth inhibitor of epithelial cell proliferation, thus, inactivation of TGF-ß1 signalling may play a role in cancer. The expression levels of TGF-ß1 and its type I and type II receptors (TßRI and TßRII) were assessed by immunohistochemical and Western blot analyses in 22 oral squamous cell carcinoma lesions, in their normal adjacent mucosa and in the squamous carcinoma cell lines FaDu and CAL27. Immunohistochemistry on 22 oral carcinomas and case-matched normal oral mucosae demonstrated that TGFß1, TßRI, and TßRII were intensively and homogeneously expressed in all normal epithelia. In contrast, TGF-ß1 and its receptors were significantly reduced in poorly (G3) differentiated tumors as compared to moderately (G2) and well differentiated (G1) lesions (p=2.8x10-3, p=1.3x10-3, p=2.8x10-3 and p=1.3x10-3, respectively). The progressive reduction of the expression levels was confirmed by Western blotting. The oral squamous carcinoma cell lines Cal27 and FaDu demonstrated a reduced and a lack of TßRI expression, respectively. A significant decrease of TßRII expression, as compared to Cal27 cells, was shown in FaDu cells. Thus, the decreased expression of TßRII combined with the absence of TßRI could account for the resistance of FaDu cells to the growth-inhibiting effect of TGF-ß1. TGF-ß1 and TGF-ß1 receptor expression significantly decreased as tumors became less differentiated and thus more aggressive, suggesting a functional role of these molecules in oral tumor progression.