title: Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis.
abstract: Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.
authors.affiliation: Airway Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and atochina@mail.med.upenn.edu.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Atochina-Vasserman
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Elena
authors.initials: E
authors.lastname: Abramova
authors.affiliation: Airway Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Melane L
authors.initials: ML
authors.lastname: James
authors.affiliation: Airway Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Ryan
authors.initials: R
authors.lastname: Rue
authors.affiliation: Airway Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Liu
authors.affiliation: Airway Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Nathan Tessema
authors.initials: NT
authors.lastname: Ersumo
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Guo
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.affiliation: Airway Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Vera P
authors.initials: VP
authors.lastname: Krymskaya
mesh_terms: D000818:Animals; D000077784:Axitinib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007093:Imidazoles; D007191:Indazoles; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042643:Vascular Endothelial Growth Factor D; D000077784:Axitinib; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: TCS2-null; VEGF-D; animal models; axitinib; lymphangiogenesis