Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis.

Abstract

Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most frequent cancer worldwide. HNSCC cell lines are typically refractory to transforming growth factor-beta (TGF-beta)-mediated cell cycle arrest. A number of these cell lines carry inactivating mutations of the TGF-beta type II (TbetaR-II) receptor, and fail to phosphorylate receptor-associated Smads, Smad2 and Smad3. In addition, we identified several intragenic mutations of the TbetaR-I gene in a small series of metastatic HNSCC specimens, suggesting that disruptions of TGF-beta signaling might contribute to the development and progression of HNSCC. To test this idea, we have now embarked on a larger scale analysis of the patterns of expression and activation of Smads in 170 HNSCC specimens assembled in tissue microarrays. Smad2 protein was expressed by 99% (95% CI: 96-100%) of tumors. The activated form of Smad2, pSmad2, was expressed in 86% (95% CI: 80-91%) of HNSCC, indicating their ability to survive and proliferate in spite of the presence of bioactive TGF-beta within the tissue microenvironment. In the 24 remaining cases (14%; 95% CI: 9-20%), pSmad2 was not detected in the tumor cells, although it was expressed by surrounding stromal cells and capillaries. In addition, 38 tumors (22%; 95% CI: 16-29%) failed to express Smad4 protein. Thus, we found evidence of loss of TGF-beta/Smad signaling in approximately 15-20% of HNSCC specimens, which is consistent with the phenotype of established human SCC lines. Moreover, we found that these Smad signaling defects were associated with a greater tendency for metastatic spread and regional or distant recurrence of HNSCC. These results indicate that inactivation of TGF-beta/Smad signaling occurs frequently in HNSCC and might have an adverse effect on patient outcome.

• Authors: Wen Xie, Savita Bharathy, David Kim, Bruce G Haffty, David L Rimm, Michael Reiss
• Journal: Oncology research (Oncol Res) Vol. 14 Issue 2 Pg. 61-73 ( 2003) ISSN: 0965-0407 [Print] United States
• PMID: 14649540 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• SMAD2 protein, human
• SMAD3 protein, human
• SMAD4 protein, human
• Smad2 Protein
• Smad3 Protein
• Smad4 Protein
• Trans-Activators
• Transforming Growth Factor beta

Topics

• Blotting, Western
• Carcinoma, Squamous Cell (metabolism, pathology)
• Cells, Cultured
• DNA-Binding Proteins (biosynthesis)
• Female
• Head and Neck Neoplasms (metabolism, pathology)
• Humans
• Immunohistochemistry
• Keratinocytes (metabolism)
• Male
• Middle Aged
• Prognosis
• Signal Transduction
• Smad2 Protein
• Smad3 Protein
• Smad4 Protein
• Trans-Activators (biosynthesis)
• Transforming Growth Factor beta (metabolism)