EGFR Kinase Promotes Acquisition of Stem Cell-Like Properties: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma Stem Cells

Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of “stemness” in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC

Mathematical methods for measuring the visually enhanced vestibulo-ocular reflex and preliminary results from healthy subjects and patient groups

Background: Visually enhanced vestibulo-ocular reflex (VVOR) is a well-known bedside clinical test to evaluate visuo-vestibular interaction, with clinical applications in patients with neurological and vestibular dysfunctions. Owing to recently developed diagnostic technologies, the possibility to perform an easy and objective measurement of the VVOR has increased, but there is a lack of computational methods designed to obtain an objective VVOR measurement. Objectives: To develop a method for the assessment of the VVOR to obtain a gain value that compares head and eye velocities and to test this method in patients and healthy subjects. Methods: Two computational methods were developed to measure the VVOR test responses: the first method was based on the area under curve of head and eye velocity plots and the second method was based on the slope of the linear regression obtained for head and eye velocity data. VVOR gain and vestibulo-ocular reflex (VOR) gain were analyzed with the data obtained from 35 subjects divided into four groups: healthy (N = 10), unilateral vestibular with vestibular neurectomy (N = 8), bilateral vestibulopathy (N = 12), and cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) (N = 5). Results: Intra-class correlation index for the two developed VVOR analysis methods was 0.99. Statistical differences were obtained by analysis of variance statistical method, comparing the healthy group (VVOR mean gain of 1 ± 0) with all other groups. The CANVAS group exhibited (VVOR mean gain of 0.4 ± 0.1) differences when compared to all other groups. VVOR mean gain for the vestibular bilateral group was 0.8 ± 0.1. VVOR mean gain in the unilateral group was 0.6 ± 0.1, with a Pearson's correlation of 0.52 obtained when VVOR gain was compared to the VOR gain of the operated side. Conclusion: Two computational methods to measure the gain of VVOR were successfully developed. The VVOR gain values appear to objectively characterize the VVOR alteration observed in CANVAS patients, and also distinguish between healthy subjects and patients with some vestibular disorders