Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer.
Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer.
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神经肽 Y 是癌细胞分泌的旁分泌因子，是结肠癌血管生成的独立调节因子。
DOI：
10.1038/s41416-022-01916-1
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发表时间：
2022
影响因子：
8.8
通讯作者：
Sarkar,Chandrani
中科院分区：
文献类型：
--
作者：
Chakroborty,Debanjan;Goswami,Sandeep;Fan,Hao;Frankel,WendyL;Basu,Sujit;Sarkar,Chandrani
背景以血管内皮生长因子-A（VEGF-A）为靶点的抗血管生成治疗的耐药性源于其他促血管生成因子介导的VEGF-A非依赖性血管生成。方法采用免疫组织化学方法检测神经肽Y（NPY）和Y 2受体（Y2 R）在结肠腺癌（CA）中的表达。原位HT 29与完整的VEGF-A基因和VEGF-A敲除（通过CRISPR/Cas9基因编辑技术）HT 29结肠癌荷瘤小鼠用特异性Y2 R拮抗剂治疗，并研究对血管生成和肿瘤生长的影响。NPY对血管生成的直接影响和潜在的分子机制阐明了结肠内皮细胞（CEC）上表达的Y2 R受体的调制。结果表明，NPY和Y2 R在人CA，原位HT 29中过表达，最有趣的是在VEGF-A耗尽原位HT 29肿瘤。用Y2 R拮抗剂治疗抑制血管生成，从而抑制HT 29肿瘤生长。阻断/沉默Y2 R废除了NPY诱导的CEC血管生成潜力。机械地，NPY调节的ERK/MAPK信号通路的激活在CEC.ConclusionsNPY来自癌细胞独立调节CA血管生成通过Y2 R存在于CEC。因此，靶向NPY/Y2 R成为CA的一种新的潜在治疗策略。
BackgroundResistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets.MethodsNeuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC).ResultsThe results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC.ConclusionsNPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.