TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

Abstract

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.

IL-6 Cooperates with G-CSF To Induce Protumor Function of Neutrophils in Bone Marrow by Enhancing STAT3 Activation

“…On the antiangiogenic side, neutrophils could adhere to the vascular endothelium, causing endothelial damage by releasing proteolytic enzymes and producing oxidants (2), the representatives of which are NE and HOCl (4). Neutrophils may also suppress angiogenesis by producing TRAIL, which could induce vascular disruption and inhibit the production of VEGF from tumor cells (10,11). Therefore, the attenuated release of NE, MPO, and TRAIL is in favor of a proangiogenic effect of neutrophils.…”

“…TRAIL not only induces apoptosis in tumor cells (9) but also has the potential to inhibit tumor angiogenesis (10,11). MPO catalyzes the formation of HOCl (12).…”

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

“…22 Because TWEAK promotes angiogenesis 21 and TRAIL inhibits it, 76 there is the intriguing possibility that Fn14-TRAIL may inhibit angiogenesis at inflammatory sites by a dual mechanism, that is, by antagonizing TWEAK's proangiogenic activity and synergistically reinforcing this effect through TRAIL's anti-angiogenic activity.…”

Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis

“…It is a fundamental step in the transition of tumors from a dormant state to a malignant state followed by its potential metastasizing to different organs (Cantarella et al, 2006; and the references therein). Inhibiting the angiogenesis and metastasis of human CaP cells could serve as an effective strategy against the progression of CaP.…”