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

Molecular Cancer

Research

Gunter Schuch¹  Jasmin Wellbrock¹  Jessica Hauschild¹  Marianne Klokow¹  Walter Fiedler¹  Carsten Bokemeyer¹  Leticia Oliveira-Ferrer²  Udo Bartsch³  Eva Maria Murga Penas⁴ 

[1] Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg (UCCH), Universtity Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg (UCCH), Universtity Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Gynecology University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Human Genetics, Christian-Albrechts-University of Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany;

关键词: Gliobastoma;    Angiogenesis;    Endostatin;    Tumstatin;    Prolactin receptor;   

DOI  :  10.1186/1476-4598-12-144

 received in 2012-11-20, accepted in 2013-11-13,  发布年份 2013

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Oliveira-Ferrer et al.; licensee BioMed Central Ltd. 2013