title: Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling.
abstract: Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.
authors.affiliation: Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Shaogang
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Haige
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: McHugh
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Bergin
authors.affiliation: Department of Pathology, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Adams
authors.affiliation: Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address: guanjl@uc.edu.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008204:Lymphangiosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D000077004:Tuberous Sclerosis Complex 1 Protein; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; D046912:Multiprotein Complexes; C489428:Myc protein, mouse; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases