The role of transforming growth factor-beta receptors in cancer of the upper aero-digestive tract

Background. Transforming growth factor-beta (TGF beta) is the most potent known physiological inhibitor of cell cycle progression of epithelial cells and stimulates the deposition of extracellular matrix. Most carcinomas derived from upper aero-digestive tract tumors are refractory to TGF beta-mediated growth arrest. We have investigated the possibility that TGF beta-resistance might be due to inactivation of TGF beta receptor genes (T beta R). Results. We have identified several head-and-neck cancer cell lines which had undergone C-to-G transversions resulting in aminoacid substitutions at highly conserved sites within the serine-threonine kinase domain of T beta R-II. One of these mutant proteins appears to have lost kinase activity, whereas, in the second case, the T beta R-II kinase appears to be constitutively activated, resulting in increased levels of plasminogen activator inhibitor-1 production. One third of primary esophageal tumor specimens failed to express T beta R-II mRNA. There was no apparent relationship with histological subtype, pathological tumor stage, or survival. Conclusion. These genetic alterations of the T beta R-II gene are likely to cause aero-digestive tract cancers to escape from TGF beta-mediated cell cycle arrest. These findings may have prognostic and therapeutic implications for the management of cancers of the upper aero-digestive tract.