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Cancer Res. 2017 Mar 15;77(6):1492-1502. doi: 10.1158/0008-5472.CAN-16-2755. Epub 2017 Feb 15.

Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation.

Author information

1
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
2
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
3
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
4
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. sel-chemaly@partners.org.

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.

PMID:
28202529
PMCID:
PMC5358967
DOI:
10.1158/0008-5472.CAN-16-2755
[Indexed for MEDLINE]
Free PMC Article

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