Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis.
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.
Xie
Wen
W
Division of Medical Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
Bharathy
Savita
S
Kim
David
D
Haffty
Bruce G
BG
Rimm
David L
DL
Reiss
Michael
M
D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta