| First Author | Muppala S | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 36 | Pages | 5189-5198 |
| PubMed ID | 28481870 | Mgi Jnum | J:247890 |
| Mgi Id | MGI:5926506 | Doi | 10.1038/onc.2017.140 |
| Citation | Muppala S, et al. (2017) Thrombospondin-4 mediates TGF-beta-induced angiogenesis. Oncogene 36(36):5189-5198 |
| abstractText | 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-beta1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-beta1 and mediates the effects of TGF-beta1 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-/- 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-beta1. We observed~3-fold increases in tumor mass and levels of angiogenesis markers in animals injected with TGF-beta1, and these effects did not occur in Thbs4-/- animals. Injections of an inhibitor of TGF-beta1 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-beta1. 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. |
