Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide.
A neuropeptide, calcitonin gene-related peptide (CGRP), is widely distributed in neuronal systems and exhibits numerous biological activities. Using CGRP-knockout mice (CGRP(-/-)), we examined whether or not endogenous CGRP facilitates angiogenesis indispensable to tumor growth. CGRP increased tube formation by endothelial cells in vitro and enhanced sponge-induced angiogenesis in vivo. Tumor growth and tumor-associated angiogenesis in CGRP(-/-) implanted with Lewis lung carcinoma (LLC) cells were significantly reduced compared with those in wild-type (WT) mice. A CGRP antagonist, CGRP8-37 or denervation of sciatic nerves (L(1-5)) suppressed LLC growth in the sites of denervation compared with vehicle infusion or sham operation. CGRP precursor mRNA levels in the dorsal root ganglion in LLC-bearing WT were increased compared with those in non-LLC-bearing mice. This increase was abolished by denervation. The expression of VEGF in tumor stroma was down-regulated in CGRP(-/-). These results indicate that endogenous CGRP facilitates tumor-associated angiogenesis and tumor growth and suggest that relevant CGRP may be derived from neuronal systems including primary sensory neurons and may become a therapeutic target for cancers.
Toda
Masaya
M
Departments of Pharmacology and Anesthesiology, Kitasato University School of Medicine, Kanagawa 228-8555, Japan.
Suzuki
Tatsunori
T
Hosono
Kanako
K
Hayashi
Izumi
I
Hashiba
Shinichiro
S
Onuma
Yuichiro
Y
Amano
Hideki
H
Kurihara
Yukiko
Y
Kurihara
Hiroki
H
Okamoto
Hirotsugu
H
Hoka
Sumio
S
Majima
Masataka
M