Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative.
OBJECTIVE
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.


METHODS
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.
Molinolo
Alfredo A
AA
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4330, USA.
Hewitt
Stephen M
SM
Amornphimoltham
Panomwat
P
Keelawat
Somboon
S
Rangdaeng
Samraeung
S
Meneses García
Abelardo
A
Raimondi
Ana R
AR
Jufe
Rafael
R
Itoiz
María
M
Gao
Yan
Y
Saranath
Dhananjaya
D
Kaleebi
George S
GS
Yoo
George H
GH
Leak
Lee
L
Myers
Ernest M
EM
Shintani
Satoru
S
Wong
David
D
Massey
H Davis
HD
Yeudall
W Andrew
WA
Lonardo
Fulvio
F
Ensley
John
J
Gutkind
J Silvio
JS
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000032:analysis; D066246:ErbB Receptors / Q000032:analysis; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis / Q000379:methods*; D014157:Transcription Factors / Q000032:analysis*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis