Bombesin induces angiogenesis and neuroblastoma growth

Abstract

Gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BBS), is a trophic factor for highly vascular neuroblastomas; its mechanisms of action in vivo are unknown. We sought to determine the effects of BBS on the growth of neuroblastoma xenografts and on angiogenesis. BBS significantly increased the growth of SK-N-SH and BE(2)-C human neuroblastomas; tumors demonstrated increased expression of angiogenic markers, PECAM-1 and VEGF, as well as phosphorylated (p)-Akt levels. RC-3095, a BBS/GRP antagonist, attenuated BBS-stimulated tumor growth and angiogenesis in vivo. GRP or GRPR silencing significantly inhibited VEGF as well as p-Akt and p-mTOR expression in vitro. Our findings demonstrate that BBS stimulates neuroblastoma growth and the expression of angiogenic markers. Importantly, these findings suggest that novel therapeutic agents, targeting BBS-mediated angiogenesis, may be useful adjuncts in patients with advanced-stage neuroblastomas.

Strong humoral response elicited by a DNA vaccine targeting gastrin-releasing peptide with optimized adjuvants inhibits murine prostate carcinoma growth in vivo

“…GRP has been reported to stimulate pro-angiogenic gene expression as well as the expression of various angiogenic markers including platelet-endothelial cell adhesion molecule (PECAM-1), vascular endothelial growth factor (VEGF) and phosphorylated-Akt levels (Kang et al 2007). Moreover, GRP or GRPR silencing has been reported to significantly suppress tumor progression and vascularization (Cornelio et al 2007).…”

Immunopreventive Effects against Murine H22 Hepatocellular Carcinoma in vivo by a DNA Vaccine Targeting a Gastrin-Releasing Peptide

“…By activating its receptors (GRPR) located on both tumor and endothelial cells, GRP is also a direct angiogenic factor as shown by in vitro and in vivo angiogenic assays (Martinez et al, 2005). In addition, GRP is able to contribute indirectly to tumor angiogenesis by augmenting expression of pro-angiogenic factors such as IL-8 and VEGF (Kang et al, 2007;. The GRP antagonist, 77427, markedly inhibits endothelial cell cord formation in vitro and inhibits angiogenesis in vivo (Levine et al, 2003).…”

“…On the other hand, Gastrin-releasing peptide is known to stimulate pro-angiogenic gene expression as well as the expression of various angiogenic markers such as vascular endothelial growth factor (Kang et al, 2007). In addition, it has been shown that GRP or GRPR silencing significantly suppress tumor progression and vascularization (Cornelio et al, 2007).…”

Specific Antibodies Elicited by a Novel DNA Vaccine Targeting Gastrin-Releasing Peptide Inhibit Murine Melanoma Growth In Vivo

“…High titers of GRPspecific antibodies could neutralize elevated levels of the GRP Studies have demonstrated that GRP could contribute to the increased metastatic potential of cancers through the stimulation of proangiogenic gene expression. GRP has been reported to stimulate GPRR-induced NF-B activation and upregulation of interleukin-8 gene expression (20) as well as the expression of various angiogenic markers, including PECAM-1 and VEGF, and to increase phosphorylated Akt levels (14). To our knowledge, our study is the first to demonstrate that immune responses induced by the pCR3.1-VS-HSP65-TP-GRP6-M2 anti-GRP vaccine significantly reduced tumor-associated angiogenesis and vascularization of solid tumors.…”

“…The GRP receptor (GRPR) is expressed aberrantly in various cancer cells (23), and GRP binding appears to activate multiple cellular signaling pathways, resulting in cellular proliferation and tumor formation (2,8). Moreover, bombesin-like peptide (BLP) family members are involved in many steps of tumor progression, including angiogenesis (9,14,20) and distant metastasis (19,22), resulting in increased aggressiveness and poorer prognosis of tumors.…”