Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative
Abstract
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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mTOR activation is one of the most frequent events in human malignancies arising from the epithelial cells lining the oral mucosa, tongue and pharynx (HNSCC).
“mTOR activation is one of the most frequent events in human malignancies arising from the epithelial cells lining the oral mucosa, tongue and pharynx, collectively referred to as head and neck squamous cell carcinomas (HNSCC) (Molinolo et al., 2007).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Molinolo et al., 2007
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Iglesias-Bartolome, R., Patel, V., Cotrim, A., Leelahavanichkul, K., Molinolo, A. A., Mitchell, J. B., & Gutkind, J. S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.06.007 · Cited by 284 · see citing works
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- Authors
- Molinolo, A. A., Hewitt, S. M., Amornphimoltham, P., Keelawat, S., Rangdaeng, S., Meneses García, A., Raimondi, A. R., Jufe, R., Itoiz, M., Gao, Y., Saranath, D., Kaleebi, G. S., Yoo, G. H., Leak, L., Myers, E. M., Shintani, S., Wong, D., Massey, H. D., Yeudall, W. A., Lonardo, F., Ensley, J., & Gutkind, J. S.
- Affiliations
- National Institutes of Health (US)
- National Institute of Dental and Craniofacial Research (US)
- Chulalongkorn University (TH)
- 4Department of Pathology, Faculty of Medicine, Chieng Mai University, Chieng Mai, Thailand;
- 5Patología, Instituto Nacional de Cancerología, Mexico DF, Mexico;
- Universidad de Buenos Aires (AR)
- 7Department of Pathology, University of Buenos Aires School of Dentistry, Buenos Aires, Argentina;
- Peking University (CN)
- Reliance Industries (India) (IN)
- Sefako Makgatho Health Sciences University (ZA)
- Wayne State University (US)
- Howard University (US)
- Ehime University (JP)
- University of California, Los Angeles (US)
- Virginia Commonwealth University (US)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2007-09-01
- Volume
- 13
- Issue
- 17
- Pages
- 4964-4973
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2103799963
- Cited by
- 243
- References
- 70
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 12 · 2023: 12 · 2022: 5 · 2021: 9 · 2020: 9 · 2019: 14 · 2018: 5 · 2017: 11 · 2016: 12 · 2015: 13 · 2014: 24 · 2013: 24 · 2012: 28
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (R01 DE-15970, R01DE015970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- Akt/mTOR signaling, head and neck squamous cell carcinoma, oral squamous cell carcinoma, tissue microarray, phospho-specific antibodies, epidermal growth factor receptor, mutant p53, targeted therapy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Carcinoma, Squamous Cell, Head and Neck Neoplasms, Humans, Immunohistochemistry, Proteins, Transcription Factors, Signal Transduction, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Tissue Array Analysis, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, Cyclooxygenase 2, TOR Serine-Threonine Kinases, ErbB Receptors
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