A Vascular Model of Tsc1 Deficiency Accelerates Renal Tumor Formation with Accompanying Hemangiosarcomas
| Autor: | Jarrett D. Leech, Neil Auricchio, Sam Goldman, Roderick T. Bronson, David J. Kwiatkowski, Stephen H.T. Lammers, Mustafa Sahin |
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| Rok vydání: | 2015 |
| Předmět: |
Vascular Endothelial Growth Factor A
Dopamine and cAMP-Regulated Phosphoprotein 32 congenital hereditary and neonatal diseases and abnormalities Cancer Research Cystadenoma Hemangiosarcoma mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Tuberous Sclerosis Complex 1 Protein Article Mice Tuberous sclerosis In vivo Genetic model Conditional gene knockout medicine Animals Molecular Biology Sirolimus Kidney Antibiotics Antineoplastic TOR Serine-Threonine Kinases Tumor Suppressor Proteins Neoplasms Experimental medicine.disease Kidney Neoplasms Up-Regulation medicine.anatomical_structure Oncology Multiprotein Complexes Cancer research TSC1 Injections Intraperitoneal Signal Transduction |
| Zdroj: | Molecular Cancer Research. 13:548-555 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Tuberous sclerosis complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumor suppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mouse model (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age, the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Because paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug testing for therapies of TSC-related tumors. Implications: These findings provide a strong rationale for simultaneous use of this conditional knockout mouse as an in vivo genetic model while seeking new cancer therapies for TSC-related tumors. Mol Cancer Res; 13(3); 548–55. ©2014 AACR. |
| Databáze: | OpenAIRE |
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