Oncotarget

Priority Research Papers:

Role of aberrant PI3K pathway activation in gallbladder tumorigenesis

Andrea Lunardi, Kaitlyn A. Webster, Antonella Papa, Bhavik Padmani, John G. Clohessy, Roderick T. Bronson, Pier Paolo Pandolfi _

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Oncotarget. 2014; 5:894-900. https://doi.org/10.18632/oncotarget.1808

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Abstract

Andrea Lunardi1, Kaitlyn A. Webster1, Antonella Papa1, Bhavik Padmani2, John G. Clohessy2, Roderick T. Bronson3 and Pier Paolo Pandolfi1

1 Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

2 Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

3 The Dana Farber/Harvard Comprehensive Cancer Center, Boston MA, USA.

Correspondence:

Pier Paolo Pandolfi, email:

Keywords: PI3K, PTEN, gallbladder tumorigenesis, mouse model.

Received: February 8, 2014 Accepted: March 8, 2014 Published: March 10, 2014

Abstract

The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to “trunkular” mutations.


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