Thrombospondin-4 mediates TGF-[beta]-induced angiogenesis

TGF-[beta] is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-[beta] signaling are process-and stage-dependent, and it is not uncommon that TGF-[beta] exerts distinct and...

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Bibliographic Details
Published in:Oncogene 2017-09, Vol.36 (36), p.5189
Main Authors: Muppala, S, Xiao, R, Krukovets, I, Verbovetsky, D, Yendamuri, R, Habib, N, Raman, P, Plow, E, Stenina-Adognravi, O
Format: Article
Language:English
Subjects:
Angiogenesis
Animal models
Cancer
Carcinogenesis
Cell growth
Cell proliferation
Cellular signal transduction
Cytokines
Endothelial cells
Extracellular matrix
Genetic aspects
Glycoproteins
Health aspects
Neovascularization
Protein biosynthesis
Smad3 protein
Thrombospondin
Transforming growth factor-b1
Transforming growth factors
Tumors
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Summary:TGF-[beta] is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-[beta] signaling are process-and stage-dependent, and it is not uncommon that TGF-[beta] exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-[beta] are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-[beta]1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-[beta]1 and mediates the effects of TGF-[beta]1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of TSP-4, and is mediated by activation of SMAD3. Using Thbs4[sup.-/-] mice and TSP-4 shRNA, we found that TSP-4 mediated pro-angiogenic functions in cultured EC and angiogenesis in vivo in response to TGF-[beta]1. We observed~3-fold increases in tumor mass and levels of angiogenesis markers in animals injected with TGF-[beta]1, and these effects did not occur in Thbs4[sup.-/-] animals. Injections of an inhibitor of TGF-[beta]1 signaling SB-431542 also decreased the weights of tumors and cancer angiogenesis. Our results from in vivo angiogenesis models and cultured EC document that TSP-4 mediates upregulation of angiogenesis by TGF-[beta]1. Upregulation of pro-angiogenic TSP-4 and selective effects of TSP-4 on EC may contribute to stimulation of tumor growth by TGF-[beta] despite the inhibition of cancer cell proliferation. Oncogene (2017) 36, 5189-5198; doi: 10.1038/onc.2017.140; published online 8 May 2017
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2017.140