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Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Authors' Affiliations: ¹ Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research and ² Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ³ Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; ⁴ Department of Pathology, Faculty of Medicine, Chieng Mai University, Chieng Mai, Thailand; ⁵ Patología, Instituto Nacional de Cancerología, Mexico DF, Mexico; ⁶ Laboratorio de Patología and ⁷ Department of Pathology, University of Buenos Aires School of Dentistry, Buenos Aires, Argentina; ⁸ Department of Oral Pathology, Peking University School of Stomatology, Beijing, China; ⁹ Reliance Life Sciences, Molecular Diagnostics and Genetics, Reliance Industries Ltd., Mumbai, India; ¹⁰ Medical University of Southern Africa (MEDUNSA), Limpopo, South Africa; ¹¹ Department of Otolaryngology-Head & Neck Surgery and Oncology, Wayne State University, Detroit, Michigan; ¹² College of Medicine, Howard University, Washington, District of Columbia; ¹³ Ehime University School of Medicine, Ehime, Japan; ¹⁴ School of Dentistry, University of California at Los Angeles, California; and ¹⁵ Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: J. Silvio Gutkind, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, Building 30, Room 212, Bethesda, MD 20892-4330. Phone: 301-496-6259; E-mail: sg39v{at}nih.gov.

Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma.

Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array.

Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR.

Conclusions: These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.

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