改良 C 型钠尿肽可使肿瘤血管正常化,重振抗肿瘤免疫力,并改善实体瘤疗法。

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-08-21 DOI:10.1126/scitranslmed.adn0904
Zhen Lu, Ioannis Verginadis, Motofumi Kumazoe, Gerardo M. Castillo, Yao Yao, Rebecca E. Guerra, Sandra Bicher, Menghao You, George McClung, Rong Qiu, Zebin Xiao, Zhen Miao, Subin S. George, Daniel P. Beiting, Takashi Nojiri, Yasutake Tanaka, Yoshinori Fujimura, Hiroaki Onda, Yui Hatakeyama, Akiko Nishimoto-Ashfield, Katrina Bykova, Wei Guo, Yi Fan, Nikolay M. Buynov, J. Alan Diehl, Ben Z. Stanger, Hirofumi Tachibana, Terence P. Gade, Ellen Puré, Constantinos Koumenis, Elijah M. Bolotin, Serge Y. Fuchs
{"title":"改良 C 型钠尿肽可使肿瘤血管正常化,重振抗肿瘤免疫力,并改善实体瘤疗法。","authors":"Zhen Lu,&nbsp;Ioannis Verginadis,&nbsp;Motofumi Kumazoe,&nbsp;Gerardo M. Castillo,&nbsp;Yao Yao,&nbsp;Rebecca E. Guerra,&nbsp;Sandra Bicher,&nbsp;Menghao You,&nbsp;George McClung,&nbsp;Rong Qiu,&nbsp;Zebin Xiao,&nbsp;Zhen Miao,&nbsp;Subin S. George,&nbsp;Daniel P. Beiting,&nbsp;Takashi Nojiri,&nbsp;Yasutake Tanaka,&nbsp;Yoshinori Fujimura,&nbsp;Hiroaki Onda,&nbsp;Yui Hatakeyama,&nbsp;Akiko Nishimoto-Ashfield,&nbsp;Katrina Bykova,&nbsp;Wei Guo,&nbsp;Yi Fan,&nbsp;Nikolay M. Buynov,&nbsp;J. Alan Diehl,&nbsp;Ben Z. Stanger,&nbsp;Hirofumi Tachibana,&nbsp;Terence P. Gade,&nbsp;Ellen Puré,&nbsp;Constantinos Koumenis,&nbsp;Elijah M. Bolotin,&nbsp;Serge Y. Fuchs","doi":"10.1126/scitranslmed.adn0904","DOIUrl":null,"url":null,"abstract":"<div >Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 761","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies\",\"authors\":\"Zhen Lu,&nbsp;Ioannis Verginadis,&nbsp;Motofumi Kumazoe,&nbsp;Gerardo M. Castillo,&nbsp;Yao Yao,&nbsp;Rebecca E. Guerra,&nbsp;Sandra Bicher,&nbsp;Menghao You,&nbsp;George McClung,&nbsp;Rong Qiu,&nbsp;Zebin Xiao,&nbsp;Zhen Miao,&nbsp;Subin S. George,&nbsp;Daniel P. Beiting,&nbsp;Takashi Nojiri,&nbsp;Yasutake Tanaka,&nbsp;Yoshinori Fujimura,&nbsp;Hiroaki Onda,&nbsp;Yui Hatakeyama,&nbsp;Akiko Nishimoto-Ashfield,&nbsp;Katrina Bykova,&nbsp;Wei Guo,&nbsp;Yi Fan,&nbsp;Nikolay M. Buynov,&nbsp;J. Alan Diehl,&nbsp;Ben Z. Stanger,&nbsp;Hirofumi Tachibana,&nbsp;Terence P. Gade,&nbsp;Ellen Puré,&nbsp;Constantinos Koumenis,&nbsp;Elijah M. Bolotin,&nbsp;Serge Y. Fuchs\",\"doi\":\"10.1126/scitranslmed.adn0904\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"16 761\",\"pages\":\"\"},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2024-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adn0904\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adn0904","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

肿瘤微环境(TME)中氧气和营养物质的缺乏会引发异常血管生成,从而产生功能障碍和渗漏血管,无法充分灌注肿瘤组织。由此导致的缺氧、代谢紊乱的加剧以及免疫抑制性肿瘤微环境的产生,都会削弱抗癌疗法的疗效。有人建议使用精心安排的血管生成抑制剂来克服这些问题,使 TME 恢复正常。在这里,我们提出了另一种基于激动剂的正常化方法,即使用 C 型钠尿肽(dCNP)的衍生物。使用 dCNP 治疗的小鼠肿瘤组织中的多个基因表达特征受到了影响。在包括结肠癌和胰腺癌在内的几种小鼠正位和皮下实体瘤模型中,这种耐受性良好的药物可刺激高功能肿瘤血管的形成,从而减少缺氧。服用 dCNP 还能抑制细胞外基质的形成和重塑,降低肿瘤间质压力。此外,使用 dCNP 治疗还能重振抗肿瘤免疫反应。服用 dCNP 可减缓小鼠原发性肿瘤的生长并抑制其转移。此外,在化疗、放射治疗或免疫治疗方案中加入 dCNP 还能提高免疫功能健全的小鼠对实体瘤的疗效。这些结果证明了使用血管正常化激动剂改善实体瘤疗法的原理,并使 dCNP 成为此类药物中的首例。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
期刊最新文献
Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis NIT2 dampens BRD1 phase separation and restrains oxidative phosphorylation to enhance chemosensitivity in gastric cancer Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease Vagal stimulation ameliorates murine colitis by regulating SUMOylation Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1