title: A vascular model of Tsc1 deficiency accelerates renal tumor formation with accompanying hemangiosarcomas.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Jarrett D
authors.initials: JD
authors.lastname: Leech
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Stephen H T
authors.initials: SH
authors.lastname: Lammers
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Sam
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Neil
authors.initials: N
authors.lastname: Auricchio
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts. mustafa.sahin@childrens.harvard.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D003537:Cystadenoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics*; D006394:Hemangiosarcoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D007274:Injections, Intraperitoneal; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009374:Neoplasms, Experimental; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D046912:Multiprotein Complexes; C497929:Ppp1r1b protein, mouse; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus