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Role of aberrant PI3K pathway activation in gallbladder tumorigenesis
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,-bisphosph...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011591/ https://www.ncbi.nlm.nih.gov/pubmed/24658595 |
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author | Lunardi, Andrea Webster, Kaitlyn A. Papa, Antonella Padmani, Bhavik Clohessy, John G. Bronson, Roderick T. Pandolfi, Pier Paolo |
author_facet | Lunardi, Andrea Webster, Kaitlyn A. Papa, Antonella Padmani, Bhavik Clohessy, John G. Bronson, Roderick T. Pandolfi, Pier Paolo |
author_sort | Lunardi, Andrea |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4011591 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-40115912014-05-08 Role of aberrant PI3K pathway activation in gallbladder tumorigenesis Lunardi, Andrea Webster, Kaitlyn A. Papa, Antonella Padmani, Bhavik Clohessy, John G. Bronson, Roderick T. Pandolfi, Pier Paolo Oncotarget Priority Research Paper 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. Impact Journals LLC 2014-03-10 /pmc/articles/PMC4011591/ /pubmed/24658595 Text en Copyright: © 2014 Lunardi et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Lunardi, Andrea Webster, Kaitlyn A. Papa, Antonella Padmani, Bhavik Clohessy, John G. Bronson, Roderick T. Pandolfi, Pier Paolo Role of aberrant PI3K pathway activation in gallbladder tumorigenesis |
title | Role of aberrant PI3K pathway activation in gallbladder tumorigenesis |
title_full | Role of aberrant PI3K pathway activation in gallbladder tumorigenesis |
title_fullStr | Role of aberrant PI3K pathway activation in gallbladder tumorigenesis |
title_full_unstemmed | Role of aberrant PI3K pathway activation in gallbladder tumorigenesis |
title_short | Role of aberrant PI3K pathway activation in gallbladder tumorigenesis |
title_sort | role of aberrant pi3k pathway activation in gallbladder tumorigenesis |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011591/ https://www.ncbi.nlm.nih.gov/pubmed/24658595 |
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