The prognosis of patients with sinonasal cancer is generally poor, and has not changed substantially over the last 3 decades.

Smad4 is a central mediator of TGF-β signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4 -/-mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited severe inflammation, which was associated with increased expression of TGF-β1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

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The prognosis of head-and-neck squamous cell carcinoma (HNSCC) has not been improved in the past 20 years. Validation of HNSCC biomarkers for targeted therapy has been hindered by a lack of animal models mimicking human HNSCC at both the pathological and molecular levels. Here we report that overexpression of K-ras or H-ras and loss of transforming growth factor-␤ type II receptor (TGF␤RII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGF␤RII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases. These tumors displayed pathology indistinguishable from human HNSCCs and exhibited multiple molecular alterations commonly found in human HNSCCs. Additionally, elevated endogenous TGF␤1 in these lesions contributed to inflammation and angiogenesis. Our data suggest that targeting common oncogenic pathways in tumor epithelia together with blocking the effect of TGF␤1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.[Keywords: HNSCC; head-and-neck-specific knockout; metastasis; Ras; TGF␤RII; TGF␤1] Supplemental material is available at http://www.genesdev.org.

Risk factors for increasing epistaxis severity in patients with HHT include frequency, duration, and intensity of episodes; invasiveness of prior therapy required to stop epistaxis; anemia; and the need for blood transfusion. From these factors, an epistaxis severity score will be presented.

In the present study, we show that transforming growth factor ␤1 (TGF-␤1) was frequently overexpressed in human head and neck squamous cell carcinomas (HNSCCs) and adjacent tissues in comparison with normal head and neck tissues. To determine the role of TGF-␤1 overexpression in HNSCC carcinogenesis, we generated transgenic mice in which TGF-␤1 transgene expression can be induced in head and neck epithelia. TGF-␤1 transgene induction in head and neck epithelia, at levels similar to those in human HNSCCs, caused severe inflammation and angiogenesis. Consequently, TGF-␤1-transgenic epithelia exhibited hyperproliferation. These phenotypes correlated with enhanced Smad signaling in transgenic epithelia and stroma. Our study suggests that TGF-␤1 overexpression at early stages of HNSCC formation provides a tumor promoting microenvironment.

Background Environmental factors such as inhaled pollutants like cigarette smoke may play a significant role in diseases of the upper airway including chronic rhinosinusitis (CRS). The objectives of this review are to summarize prior studies that describe the correlation between active smoking and second-hand smoke (SHS) on CRS. We also review the pathophysiologic effects of cigarette smoke on sinonasal mucosa and discuss its impact on surgical outcomes of endoscopic sinus surgery (ESS). Methods A literature search was conducted with the PUBMED database using the terms “sinusitis” or “rhinosinusitis” and “smoking”. Additional search terms of “nasal epithelial” and “smoke” were used to find articles which discussed pathophysiologic effects of tobacco smoke while “second-hand smoke” was added to identify articles analyzing the correlation of SHS and CRS. Finally “endoscopic sinus surgery” and “outcomes” were linked to “smoking” to find articles that analyzed the impact of smoking on surgical results. Results 204 articles were identified in the initial search. An additional 72 articles were reviewed for their relevance to the pathophysiologic effects of tobacco smoke while 31 papers were analyzed to determine the correlation of SHS and CRS. Twenty-nine papers were reviewed to analyze the impact of smoking on surgical results. Conclusion There is clear evidence in the literature that cigarette smoke, either through active smoking or passive exposure to SHS, contributes to CRS. Recent prospective studies suggest that active smoking is not a contraindication to ESS while the impact of smoking volume and long-term smoking after ESS has not been sufficiently evaluated.

Nasal polyps appear to have characteristic transcriptional signatures compared to normal sinonasal mucosa. The five genes identified in this study likely play roles in the pathogenesis of polyps associated with CRS and ASA, and are therefore attractive targets for novel medical therapies for these common debilitating diseases.