Priority Research Papers:
Role of aberrant PI3K pathway activation in gallbladder tumorigenesis
Metrics: PDF 1386 views | HTML 1701 views | ?
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.
Pier Paolo Pandolfi, email:
Keywords: PI3K, PTEN, gallbladder tumorigenesis, mouse model.
Received: February 8, 2014 Accepted: March 8, 2014 Published: March 10, 2014
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.