Activation of the PI3K/AKT pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models
| Autor: | Annick Vieillefond, Bart O. Williams, Charis Eng, Chao-Nan Qian, Aaron Massie, Sok Kean Khoo, Vincent Molinié, Karl Dykema, Eva Comperat, Jared Knol, Kyle A. Furge, James H. Resau, Mathilde Sibony, Jindong Chen, Bin Tean Teh, Dan Huang, Kristin Vanden Beldt, Yves Denoux, Eric J. Kort, Philippe Camparo, John Anema, Richard J. Kahnoski, Hans Morreau |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Pathology medicine.medical_specialty Loss of Heterozygosity Mice Transgenic Article Immunoenzyme Techniques Mice Phosphatidylinositol 3-Kinases Renal cell carcinoma medicine Carcinoma Biomarkers Tumor PTEN Animals Humans Kidney Pelvis RNA Messenger Protein kinase B Carcinoma Renal Cell Microdissection PI3K/AKT/mTOR pathway Oligonucleotide Array Sequence Analysis Kidney biology Integrases Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Lasers TOR Serine-Threonine Kinases PTEN Phosphohydrolase Ribosomal Protein S6 Kinases 70-kDa medicine.disease Carcinoma Papillary Kidney Neoplasms medicine.anatomical_structure Oncology Urinary Bladder Neoplasms biology.protein Cancer research Female Renal pelvis Protein Kinases Proto-Oncogene Proteins c-akt |
| Zdroj: | Cancer research. 69(21) |
| ISSN: | 1538-7445 |
| Popis: | Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents. [Cancer Res 2009;69(21):8256–64] |
| Databáze: | OpenAIRE |
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