title: Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation.
abstract: Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation.Cancer Res; 77(6); 1492-502. ©2017 AACR.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Steagall
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Lamattina
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pacheco-Rodriguez
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Mario
authors.initials: M
authors.lastname: Stylianou
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Pranav
authors.initials: P
authors.lastname: Kidambi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stump
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Golzarri
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Carmen
authors.initials: C
authors.lastname: Priolo
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. sel-chemaly@partners.org.
authors.forename: Souheil
authors.initials: S
authors.lastname: El-Chemaly
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D018932:Chemokine CCL2; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042643:Vascular Endothelial Growth Factor D; D000072377:Syk Kinase