Combination therapy targeting integrins reduces glioblastoma tumor growth through antiangiogenic and direct antitumor activity and leads to activation of the pro-proliferative prolactin pathwayReportar como inadecuado




Combination therapy targeting integrins reduces glioblastoma tumor growth through antiangiogenic and direct antitumor activity and leads to activation of the pro-proliferative prolactin pathway - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Molecular Cancer

, 12:144

First Online: 20 November 2013Received: 20 November 2012Accepted: 13 November 2013DOI: 10.1186-1476-4598-12-144

Cite this article as: Oliveira-Ferrer, L., Wellbrock, J., Bartsch, U. et al. Mol Cancer 2013 12: 144. doi:10.1186-1476-4598-12-144

Abstract

BackgroundTumors may develop resistance to specific angiogenic inhibitors via activation of alternative pathways. Therefore, multiple angiogenic pathways should be targeted to achieve significant angiogenic blockade. In this study we investigated the effects of a combined application of the angiogenic inhibitors endostatin and tumstatin in a model of human glioblastoma multiforme.

ResultsInhibitors released by stably transfected porcine aortic endothelial cells PAE showed anti-angiogenic activity in proliferation and wound-healing assays with endothelial cells EC. Interestingly, combination of endostatin and tumstatin ES + Tum also reduced proliferation of glioma cells and additionally induced morphological changes and apoptosis in vitro. Microencapsulated PAE-cells producing these inhibitors were applied for local therapy in a subcutaneous glioblastoma model. When endostatin or tumstatin were applied separately, in vivo tumor growth was inhibited by 58% and 50%, respectively. Combined application of ES + Tum, in comparison, resulted in a significantly more pronounced inhibition of tumor growth 83%. cDNA microarrays of tumors treated with ES + Tum revealed an up-regulation of prolactin receptor PRLR. ES + Tum-induced up-regulation of PRLR in glioma cells was also found in in vitro. Moreover, exogenous PRLR overexpression in vitro led to up-regulation of its ligand prolactin and increased proliferation suggesting a functional autocrine growth loop in these cells.

ConclusionOur data indicate that integrin-targeting factors endostatin and tumstatin act additively by inhibiting glioblastoma growth via reduction of vessel density but also directly by affecting proliferation and viability of tumor cells. Treatment with the ES + Tum-combination activates the PRLR pro-proliferative pathway in glioblastoma. Future work will show whether the prolactin signaling pathway represents an additional target to improve therapeutic strategies in this entity.

KeywordsGliobastoma Angiogenesis Endostatin Tumstatin Prolactin receptor AbbreviationsCGTCilengitide

CMConditionated medium

ECEndothelial cells

ESEndostatin

GBMGlioblastoma Multiforme

HDMECHuman dermal microvascular endothelial cells

PAEPorcine aortic endothelial cells

PRLProlactin

PRLRProlactin receptor

TumTumstatin.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-12-144 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Autor: Leticia Oliveira-Ferrer - Jasmin Wellbrock - Udo Bartsch - Eva Maria Murga Penas - Jessica Hauschild - Marianne Klokow - Ca

Fuente: https://link.springer.com/







Documentos relacionados