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Abstract
Head and neck malignancies account for 6% of all cancers diagnosed in the United States and result in approximately 7,500 deaths annually. Head and Neck Squamous Cell Carcinomas (HNSCCs) and Adenoid Cystic Carcinomas (ACCs) comprise approximately 90% and 10% respectively of head and neck cancers.
Microarray technology was utilized to conduct a genome wide analysis of dysregulated genes in 42 HNSCCs (25 primary and 16 locally recurrent) and compared them to Normal Mucosa Controls. Our data demonstrated a highly unique, novel and specific signature of genes that predict recurrence of HNSCCs after definitive treatment (2890 genes). Several gene expression signatures were readily identifiable in the HNSCC tumors including signatures associated with proliferation, extracellular matrix production, cytokine/chemokine expression, and immune response. Of particular interest was the association of a gene expression signature enriched for genes involved in tumor invasion and metastasis with patients experiencing locally recurrent disease. These data provide evidence for a new gene expression-based biomarker of local treatment failure in HNSCC.
Adenoid Cystic Carcinoma (ACC) is a tumor of the head and neck region characterized by a propensity for distant spread and resistance to chemotherapy and conventional external beam radiation therapy. To better understand these observations on a genomic level, we performed a comprehensive survey of gene expression in ACC using microarray analysis. Our results demonstrate that ACC tumors express genes associated with early developmental processes such as neurogenesis, morphogenesis, cell proliferation, and development consistent with a dedifferentiated state. In addition, our data confirm the observation of genes previously noted be overexpressed in ACC and implicate several new genes with potential roles in the pathogenesis of ACC.
Our previous oligonucleotide microarray study identified Slug (SNAI2) over-expression in a signature associated with recurrent HNSCC following definitive treatment. Slug, a zinc finger transcription factor family member, is an important mediator of epithelial to mesenchymal transitions (EMT) in developing organisms and functions in modulating sensitivity to apoptosis. Our findings demonstrate that HNSCC cell lines engineered to over express human SLUG, show characteristic morphologic and molecular events consistent with classic EMT leading to a malignant phenotype. Furthermore, the anti-apoptotic effect of SLUG results in resistance to the effects of paclitaxel and γ-irradation. These results suggest that SLUG expression in HNSCC is an important mediator of tumor aggressiveness.
Inhibin βA subunit of Activin A, a member of the Transforming Growth Factor-Beta (TGF-β) family, was one of several genes over-expressed in HNSCC patients experiencing local regional recurrence. To further elicit the role of Inhibin βA in tumor progression we explored Activin and its receptors in HNSCC progression. Our data suggests that Activin, Inhibin βA, and its active receptor ACVRIB become altered in the progression from normal oral mucosa to leukoplakia to SCC. Proliferation data suggests that exogenous Activin confers a modest proliferative impulse in HNSCC cell lines. Finally, we show that Activin A exposure to Fadu cells increases their invasive potential.
Our data suggests that a number of genes are dysregulated in HNSCC and ACC tumors leading to their invasive potential. Genes associated with proliferation, differentiation and invasion were identified in both tumors. We further validated the invasive potential of genes (Slug and Inhibin βA) identified in recurrent HNCC tumors using HNSCC cells lines in-vitro.
