Neuronal System-dependent Facilitation of Tumor Angiogenesis and Tumor Growth by Calcitonin Gene-related Peptide

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Sep 2

PMID 18757746

Citations 60

Authors

Masaya Toda

Tatsunori Suzuki

Kanako Hosono

Izumi Hayashi

Shinichiro Hashiba

Yuichiro Onuma

Hideki Amano

Yukiko Kurihara

Hiroki Kurihara

Hirotsugu Okamoto

Sumio Hoka

Masataka Majima

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Understanding the role of nerves in head and neck cancers - a review.

Rutkowski K, Gola M, Godlewski J, Starzynska A, Marvaso G, Mastroleo F Oncol Rev. 2025; 18:1514004.

PMID: 39906323 PMC: 11791411. DOI: 10.3389/or.2024.1514004.

Neuroscience of cancer: unraveling the complex interplay between the nervous system, the tumor and the tumor immune microenvironment.

Huang Q, Hu B, Zhang P, Yuan Y, Yue S, Chen X Mol Cancer. 2025; 24(1):24.

PMID: 39825376 PMC: 11740516. DOI: 10.1186/s12943-024-02219-0.

Targeting the peripheral neural-tumour microenvironment for cancer therapy.

Yaniv D, Mattson B, Talbot S, Gleber-Netto F, Amit M Nat Rev Drug Discov. 2024; 23(10):780-796.

PMID: 39242781 DOI: 10.1038/s41573-024-01017-z.

Lack of RAMP1 Signaling Suppresses Liver Regeneration and Angiogenesis Following Partial Hepatectomy in Mice.

Nakamoto S, Ito Y, Nishizawa N, Kuroda Y, Hosono K, Kamata M In Vivo. 2024; 38(5):2261-2270.

PMID: 39187322 PMC: 11363762. DOI: 10.21873/invivo.13691.

Empowerment, Pain Control, and Quality of Life Improvement in Early Triple-Negative Breast Cancer Patients through Pain Neuroscience Education: A Prospective Cohort Pilot Study Protocol (EMPOWER Trial).

Tiberio P, Balordi M, Castaldo M, Vigano A, Jacobs F, Benvenuti C J Pers Med. 2024; 14(7).

PMID: 39063964 PMC: 11278336. DOI: 10.3390/jpm14070711.

References

Saeki T, Ohno T, Kamata K, Arai K, Mizuguchi S, Katori M . Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI2 in rats. Am J Physiol Gastrointest Liver Physiol. 2003; 286(1):G68-75. DOI: 10.1152/ajpgi.00538.2002. View

Amara S, JONAS V, Rosenfeld M, Ong E, Evans R . Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982; 298(5871):240-4. DOI: 10.1038/298240a0. View

Shindo T, Kurihara Y, Imai T, Wang Y, Morita H, Imai Y . Elevated sympathetic nervous activity in mice deficient in alphaCGRP. Circ Res. 2001; 89(11):983-90. DOI: 10.1161/hh2301.100812. View

Direkze N, Jeffery R, Hodivala-Dilke K, Hunt T, Playford R, Elia G . Bone marrow-derived stromal cells express lineage-related messenger RNA species. Cancer Res. 2006; 66(3):1265-9. DOI: 10.1158/0008-5472.CAN-05-3202. View

Holzer P . Neural emergency system in the stomach. Gastroenterology. 1998; 114(4):823-39. DOI: 10.1016/s0016-5085(98)70597-9. View

Fan T, Hu D, Guard S, GRESHAM G, Watling K . Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol. 1993; 110(1):43-9. PMC: 2176009. DOI: 10.1111/j.1476-5381.1993.tb13769.x. View

Bolos V, Grego-Bessa J, de la Pompa J . Notch signaling in development and cancer. Endocr Rev. 2007; 28(3):339-63. DOI: 10.1210/er.2006-0046. View

Mukouyama Y, Shin D, Britsch S, Taniguchi M, Anderson D . Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell. 2002; 109(6):693-705. DOI: 10.1016/s0092-8674(02)00757-2. View

Gee M, Lynn B, Cotsell B . The relationship between cutaneous C fibre type and antidromic vasodilatation in the rabbit and the rat. J Physiol. 1997; 503 ( Pt 1):31-44. PMC: 1159884. DOI: 10.1111/j.1469-7793.1997.031bi.x. View

10.

Portenoy R, Lesage P . Management of cancer pain. Lancet. 1999; 353(9165):1695-700. DOI: 10.1016/S0140-6736(99)01310-0. View

11.

Ekstrand A, Cao R, Bjorndahl M, Nystrom S, Jonsson-Rylander A, Hassani H . Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci U S A. 2003; 100(10):6033-8. PMC: 156321. DOI: 10.1073/pnas.1135965100. View

12.

Cadieux A, Monast N, Pomerleau F, Fournier A, Lanoue C . Bronchoprotector properties of calcitonin gene-related peptide in guinea pig and human airways. Effect of pulmonary inflammation. Am J Respir Crit Care Med. 1999; 159(1):235-43. DOI: 10.1164/ajrccm.159.1.9711031. View

13.

Mizuguchi S, Ohno T, Hattori Y, Kamata K, Arai K, Saeki T . Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle. J Gastroenterol Hepatol. 2005; 20(4):611-8. DOI: 10.1111/j.1440-1746.2004.03764.x. View

14.

Amano H, Ando K, Minamida S, Hayashi I, Ogino M, Yamashina S . Adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in vivo. Jpn J Pharmacol. 2002; 87(3):181-8. DOI: 10.1254/jjp.87.181. View

15.

Boku K, Ohno T, Saeki T, Hayashi H, Hayashi I, Katori M . Adaptive cytoprotection mediated by prostaglandin I(2) is attributable to sensitization of CRGP-containing sensory nerves. Gastroenterology. 2001; 120(1):134-43. DOI: 10.1053/gast.2001.20916. View

16.

Miller G . Developmental biology. Nerves tell arteries to make like a tree. Science. 2002; 296(5576):2121-3. DOI: 10.1126/science.296.5576.2121a. View

17.

Portenoy R, Payne D, Jacobsen P . Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999; 81(1-2):129-34. DOI: 10.1016/s0304-3959(99)00006-8. View

18.

Yu X, Li C, Wang K, Dai H . Calcitonin gene-related peptide regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes by activation of ERK1/2 MAPK. Regul Pept. 2006; 137(3):134-9. DOI: 10.1016/j.regpep.2006.07.001. View

19.

Arai K, Ohno T, Saeki T, Mizuguchi S, Kamata K, Hayashi I . Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide. Gut. 2003; 52(9):1242-9. PMC: 1773782. DOI: 10.1136/gut.52.9.1242. View

20.

Weihe E, Nohr D, Schafer M, Persson S, EKSTROM G, Kallstrom J . Calcitonin gene related peptide gene expression in collagen-induced arthritis. Can J Physiol Pharmacol. 1995; 73(7):1015-9. DOI: 10.1139/y95-142. View