Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide
Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide
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DOI：
10.1073/pnas.0800767105
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发表时间：
2008-09-09
影响因子：
11.1
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
--
作者：
Toda, Masaya;Suzuki, Tatsunori;Majima, Masataka
降钙素基因相关肽（calcitonin gene-related peptide，CGRP）是一种广泛分布于神经系统的神经肽，具有多种生物学活性。使用CGRP基因敲除小鼠（CGRP（-/-）），我们研究了内源性CGRP是否促进肿瘤生长所必需的血管生成。CGRP在体外增加内皮细胞的管形成，并在体内增强海绵诱导的血管生成。与野生型（WT）小鼠相比，植入刘易斯肺癌（LLC）细胞的CGRP（-/-）小鼠的肿瘤生长和肿瘤相关血管生成显著减少。CGRP拮抗剂，CGRP 8 -37或坐骨神经（L1-5）去神经支配抑制LLC生长在去神经支配的网站相比，车辆输注或假手术。携带LLC的WT中背根神经节中CGRP前体mRNA水平与非携带LLC的小鼠中的那些相比增加。这种增加被取消去神经。CGRP（-/-）组肿瘤间质VEGF表达下调。这些结果表明，内源性CGRP促进肿瘤相关的血管生成和肿瘤生长，并表明相关的CGRP可能来自神经系统，包括初级感觉神经元，并可能成为癌症的治疗靶点。
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 (L1-5) 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.