Purpose: Head and neck squamous cell carcinomas (HNSCC) are characterized by high morbidity and mortality, largely due to the high invasive and metastatic potential of these tumors, high recurrence rates, and low treatment responses. Proteinases have been implicated in several aspects of tumor growth and metastasis in a broad range of tumors including HNSCC.Experimental Design: Comprehensive expression profiling of proteinases [matrix metalloproteinases (MMPs), A disintegrin and metalloproteinase (ADAMs), and ADAMs with thrombospondin motif (ADAMTSs)] and their inhibitors [tissue inhibitor of metalloproteinases (TIMPs)] was done using quantitative real-time reverse transcription-PCR analysis of a large cohort of tissue samples representing the tumor (n = 83), the invasive margin (n = 41), and the adjacent tissue (n = 41) from 83 HNSCC patients, along with normal tissue controls (n = 13), as well as cell lines established from tumors of 34 HNSCC patients.Results: The results show specifically elevated gene expression of several proteinases, including MMP1, MMP3, MMP10, and MMP13 within tumor tissue and peritumoral adjacent tissue. In addition, the results identify several novel HNSCC-associated proteinases, including ADAM8, ADAM9, ADAM17, ADAM28, ADAMTS1, ADAMTS8, and ADAMTS15. There were also significant differences in proteinase expression based on clinical parameters, i.e., tumor location, grade, and local invasion. MMP13 expression was significantly higher in large (>4 cm) locally invasive tumors (P < 0.05). MMP9 expression was significantly decreased in tumors with regional metastasis, whereas increased expression of ADAM8 was noted in the metastatic tumors (P < 0.001 for both).Conclusions: These findings suggest the HNSCC degradome as a valuable source of diagnostic, predictive, and prognostic molecular markers for these malignant tumors. Clin Cancer Res; 16(7); 2022-35. ©2010 AACR.Head and neck squamous cell carcinoma (HNSCC) can be defined as a malignant tumor derived from the squamous epithelial cells that line the upper aerodigestive tract, which extends from the surface of the lips to the cervical surface of the esophagus. HNSCC is the fifth most common cancer worldwide and, in 2002, was the cause of over 300,000 deaths worldwide (1). The overall survival rates of HNSCC patients (∼50%) have remained unaltered for over 20 years. The presence of lymph node metastases is the single most important predictive factor for HNSCC patients resulting in a 50% decrease in survival (2, 3).The degradome comprises both the complete set of proteases (also known as peptidases and proteinases) expressed by a cell, tissue, or organism at a given time, and the substrate repertoire of a given proteinase (4). There is a well-established association between matrix proteolysis and cancer invasion and metastasis, and the proteinases of every class have been linked to malignancy and invasion of tumor cells (5). However, through the study of transgenic models and the identification of further proteinases and proteinase s...
Squamous carcinoma of the oropharynx presents with symptoms common to many benign diseases, and this can cause delay in referral to secondary care. We investigate delay in referral, defining this as the time from symptom-onset to date of general practitioners referral letter to secondary care, and the effect of that delay, using a retrospective case notes based study of patients presenting at our institution with oropharyngeal squamous carcinoma between 1995 and 2005. Using correlation analysis and ordinal regression, we examined the relationship between increased referral delay from primary care, clinical stage at presentation, and survival. Increasing time from symptom onset to referral to secondary care was positively correlated with more advanced disease stage at presentation (r s ¼ þ 0.346, P ¼ 0.004). This was confirmed with ordinal regression modelling (delay estimate ¼ 0.045, P ¼ 0.042). Patients with delay of less than 6 weeks had significantly improved survival compared to those with a delay of greater than 6 weeks (P ¼ 0.032). For every 1 week of delay in referral, we estimate that the stage of presentation will progress by 0.045 of 'a stage'.
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