Decreased expression of TGF-? cell surface receptors during progression of human oral squamous cell carcinoma

Abstract

This study examined the immunocytochemical expression of the transforming growth factor-beta (TGF-beta) isoforms TGF-beta1, TGF-beta2, and TGF-beta3, together with the TGF-beta cell surface receptors TbetaR-I and TbetaR-II, in patient-matched tissue pairs of normal human oral epithelium, primary squamous cell carcinomas, and metastatic lymph node tumour deposits. There were no significant differences in the intensity of TGF-beta isoform specific staining between the normal oral epithelium, the primary tumours, and the lymph node metastases. By contrast, there was significantly less TbetaR-II in the metastases than in the primary tumour and between the primary tumour and the normal oral epithelium. Similar trends were evident with TbetaR-I, but not at a statistically significant level. This study also examined the structure of TbetaR-I and TbetaR-II in normal human oral keratinocytes in vitro and in 14 human oral carcinoma cell lines with known responses to TGF-beta1. No structural abnormalities of TbetaR-II were present in the normal keratinocytes or in 13 of 14 malignant cell lines; in one line, there were both normal and mutant forms of TbetaR-II, the latter being in the form of a frameshift mutation with the insertion of a single adenine base (bases 709-718, codons 125-128), predicting a truncated receptor having no kinase domain. No defects were present in TbetaR-I. The structures of TbetaR-I and TbetaR-II did not correlate with growth inhibition by TGF-beta1. The data suggest that decreased expression of TGF-beta receptors, rather than structural defects of these genes, may be important in oral epithelial tumour progression. In order to examine the functional significance of a specific decrease in TbetaR-II expression, a dominant-negative TbetaR-II construct (dnTbetaR-II) was transfected into a human oral carcinoma cell line with a normal TGF-beta receptor profile and known to be markedly inhibited by TGF-beta1. In those clones that overexpressed the dnTbetaR-II, growth inhibition and Smad binding activity were decreased, whilst the regulation of Fra-1 and collagenase-1 remained unchanged following treatment with TGF-beta1. The results demonstrate that a decrease in TbetaR-II relative to TbetaR-I leads to selective gene regulation with loss of growth inhibition but continued transcription of AP-1-dependent genes that are involved in the regulation of the extracellular matrix.

Molecular mechanisms of head and neck cancer

“…Although mutations of the individual members of the TGF-β pathway have been identified in OSCC and other epithelial tumors, they are relatively rare [70][71][72][73][74]. A more frequent event is a reduction in the expression of TβRII [75]. This is evident in knockout mouse models where there is an increase in the penetrance and rate of tumor formation, and metastases in various tissues [76][77][78][79][80][81][82][83][84].…”

“…This signaling diminishes as the disease progresses from carcinoma to metastases. During this transition a significant decrease in TβRII expression, resulting from down-regulation of gene expression and not mutations, has been observed [75]. Understanding the effects of this decrease in TGF-β signaling and identifying the molecules involved in modulation of cell cycle, proliferation, survival and differentiation in response to TGF-β will help in developing novel targeted therapies for treatment of oral cancer.…”

Attenuated type II TGF‐β receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination

“…TGF-␤1-induced transcriptional activation of the SBE4-luc reporter was significantly less in the dn T␤R-II expressing lines, H400-dn T␤R-II-Clone E and H400-dn T␤R-II-Clone H, compared to controls. 10 …”

“…Mutations of T␤R-I, 5 T␤R-II, 6,7 Smad 2 8 and Smad 4 genes, 9 for example, have been reported in human oral cancer but are uncommon. What appears to occur more frequently is decreased expression of T␤R-II throughout oral epithelial tumour progression; 10 the biological consequences of this phenomenon are unknown. In transgenic animals with targeted expression of dominant-negative T␤R-II in specific tissues, there is acceleration of tumorigenesis after carcinogen treatment.…”

Reduced expression of transforming growth factor‐β receptors is an unfavorable prognostic factor in human esophageal squamous cell carcinoma

“…3,29 In esophageal carcinoma cell lines, Garrigue-Antar et al 30 reported loss of TGF-␤R-II gene expression. Although reduced expression of TGF-␤ receptor protein has been reported in several cancers, 3,31,32 no immunohistochemical studies of TGF-␤ receptors and TGF-␤1 expression in esophageal squamous cell carcinoma (SCC) have been reported. Therefore, we evaluated the association of TGF-␤ receptors and TGF-␤1 expression with pathologic characteristics and clinical outcome in patients with esophageal SCC.…”