肿瘤内皮细胞与癌细胞之间的相互作用是肿瘤转移的重要因素。

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Victor Oginga Oria, Joana Leitao Castro, Jéssica de Pina Roque, Alejandro Gutierrez Martinez, Freia Isak Jørgensen, Marie Vestergaard Lukassen, Leonor Rib, Mia Kristine Grønning Høg, Kasper Johansen Mygind, Janine Terra Erler
{"title":"肿瘤内皮细胞与癌细胞之间的相互作用是肿瘤转移的重要因素。","authors":"Victor Oginga Oria, Joana Leitao Castro, Jéssica de Pina Roque, Alejandro Gutierrez Martinez, Freia Isak Jørgensen, Marie Vestergaard Lukassen, Leonor Rib, Mia Kristine Grønning Høg, Kasper Johansen Mygind, Janine Terra Erler","doi":"10.1186/s12964-025-02441-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Metastasis is a major contributor of cancer-related mortality and involves complex crosstalk between cancer cells and stromal cells modulated by various cytokines and growth factors. While the endothelium is essential for supplying nutrients and oxygen, little is known about its role in metastasis initiation. Determining the effect of endothelial-derived angiocrine factors on cancer cells may explain the mechanisms regulating metastasis initiation.</p><p><strong>Results: </strong>In this study, we investigated the role of normal endothelial cells (NEC) and tumor endothelial cells (TEC) in regulating the rate-limiting steps of metastasis initiation. First, we demonstrated that TEC have a higher proliferation, migration, and angiogenic potential than NEC. TEC-conditioned media significantly promoted chemotaxis, invasion, and proliferation of cancer cells relative to NEC-conditioned media. Additionally, TEC facilitated faster cell-cell adhesion to tumor cells than NEC. Mass spectrometry analysis of endothelial cell secretome revealed higher levels of PDGF-AA, PDGF-C, and VEGFA in TEC-conditioned medium, which were associated with enriched PI3K-AKT, MAPK, and RAS signaling pathways, as well as regulation of actin cytoskeleton and focal adhesion. In vitro functional studies using recombinant proteins showed that PDGF-AA and PDGF-C significantly promoted cancer cell chemotaxis and invasion without affecting proliferation. However, unlike VEGFA, PDGF-AA and PDGF-C did not affect endothelial cell tube formation or vascular permeability. Interestingly, neutralization of TEC-derived PDGF-C signficantly inhibited tumor cell chemotaxis and invasion, and attenuated EphA2/AKT/P38/ERK signaling in vitro. In vivo, the co-injection of TEC and 4T1 cells resulted in significantly higher primary breast tumor growth and liver metastasis in an orthotopic mouse model.</p><p><strong>Conclusion: </strong>Our results demonstrate that crosstalk between cancer cells and TEC, partly through angiocrine factors in the TME, induces the rate-limiting steps of metastasis initiation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"443"},"PeriodicalIF":8.2000,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Crosstalk between tumor endothelial cells and cancer cells is important for metastasis initiation.\",\"authors\":\"Victor Oginga Oria, Joana Leitao Castro, Jéssica de Pina Roque, Alejandro Gutierrez Martinez, Freia Isak Jørgensen, Marie Vestergaard Lukassen, Leonor Rib, Mia Kristine Grønning Høg, Kasper Johansen Mygind, Janine Terra Erler\",\"doi\":\"10.1186/s12964-025-02441-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Metastasis is a major contributor of cancer-related mortality and involves complex crosstalk between cancer cells and stromal cells modulated by various cytokines and growth factors. While the endothelium is essential for supplying nutrients and oxygen, little is known about its role in metastasis initiation. Determining the effect of endothelial-derived angiocrine factors on cancer cells may explain the mechanisms regulating metastasis initiation.</p><p><strong>Results: </strong>In this study, we investigated the role of normal endothelial cells (NEC) and tumor endothelial cells (TEC) in regulating the rate-limiting steps of metastasis initiation. First, we demonstrated that TEC have a higher proliferation, migration, and angiogenic potential than NEC. TEC-conditioned media significantly promoted chemotaxis, invasion, and proliferation of cancer cells relative to NEC-conditioned media. Additionally, TEC facilitated faster cell-cell adhesion to tumor cells than NEC. Mass spectrometry analysis of endothelial cell secretome revealed higher levels of PDGF-AA, PDGF-C, and VEGFA in TEC-conditioned medium, which were associated with enriched PI3K-AKT, MAPK, and RAS signaling pathways, as well as regulation of actin cytoskeleton and focal adhesion. In vitro functional studies using recombinant proteins showed that PDGF-AA and PDGF-C significantly promoted cancer cell chemotaxis and invasion without affecting proliferation. However, unlike VEGFA, PDGF-AA and PDGF-C did not affect endothelial cell tube formation or vascular permeability. Interestingly, neutralization of TEC-derived PDGF-C signficantly inhibited tumor cell chemotaxis and invasion, and attenuated EphA2/AKT/P38/ERK signaling in vitro. In vivo, the co-injection of TEC and 4T1 cells resulted in significantly higher primary breast tumor growth and liver metastasis in an orthotopic mouse model.</p><p><strong>Conclusion: </strong>Our results demonstrate that crosstalk between cancer cells and TEC, partly through angiocrine factors in the TME, induces the rate-limiting steps of metastasis initiation.</p>\",\"PeriodicalId\":55268,\"journal\":{\"name\":\"Cell Communication and Signaling\",\"volume\":\"23 1\",\"pages\":\"443\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Communication and Signaling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s12964-025-02441-3\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12964-025-02441-3","RegionNum":2,"RegionCategory":"生物学","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

背景:转移是癌症相关死亡的主要原因,涉及多种细胞因子和生长因子调节的癌细胞和基质细胞之间的复杂串扰。虽然内皮对于提供营养和氧气是必不可少的,但对其在转移起始中的作用知之甚少。确定内皮来源的血管分泌因子对癌细胞的影响可能解释调节转移起始的机制。结果:在本研究中,我们研究了正常内皮细胞(NEC)和肿瘤内皮细胞(TEC)在调节转移起始的限速步骤中的作用。首先,我们证明了TEC比NEC具有更高的增殖、迁移和血管生成潜力。相对于nec条件培养基,tec条件培养基显著促进癌细胞的趋化性、侵袭和增殖。此外,TEC比NEC能更快地促进细胞与肿瘤细胞的粘附。内皮细胞分泌组质谱分析显示,tec条件培养基中PDGF-AA、PDGF-C和VEGFA水平较高,这与PI3K-AKT、MAPK和RAS信号通路的富集以及肌动蛋白细胞骨架和局灶黏附的调节有关。重组蛋白的体外功能研究表明,PDGF-AA和PDGF-C显著促进癌细胞趋化和侵袭,但不影响增殖。然而,与VEGFA不同,PDGF-AA和PDGF-C不影响内皮细胞管的形成或血管通透性。有趣的是,中和tec来源的PDGF-C可显著抑制肿瘤细胞趋化性和侵袭,并减弱EphA2/AKT/P38/ERK信号。在体内,在原位小鼠模型中,TEC和4T1细胞共同注射可显著提高原发性乳腺肿瘤的生长和肝脏转移。结论:我们的研究结果表明,癌细胞与TEC之间的串扰,部分通过TME中的血管分泌因子,诱导了转移起始的限速步骤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Crosstalk between tumor endothelial cells and cancer cells is important for metastasis initiation.

Background: Metastasis is a major contributor of cancer-related mortality and involves complex crosstalk between cancer cells and stromal cells modulated by various cytokines and growth factors. While the endothelium is essential for supplying nutrients and oxygen, little is known about its role in metastasis initiation. Determining the effect of endothelial-derived angiocrine factors on cancer cells may explain the mechanisms regulating metastasis initiation.

Results: In this study, we investigated the role of normal endothelial cells (NEC) and tumor endothelial cells (TEC) in regulating the rate-limiting steps of metastasis initiation. First, we demonstrated that TEC have a higher proliferation, migration, and angiogenic potential than NEC. TEC-conditioned media significantly promoted chemotaxis, invasion, and proliferation of cancer cells relative to NEC-conditioned media. Additionally, TEC facilitated faster cell-cell adhesion to tumor cells than NEC. Mass spectrometry analysis of endothelial cell secretome revealed higher levels of PDGF-AA, PDGF-C, and VEGFA in TEC-conditioned medium, which were associated with enriched PI3K-AKT, MAPK, and RAS signaling pathways, as well as regulation of actin cytoskeleton and focal adhesion. In vitro functional studies using recombinant proteins showed that PDGF-AA and PDGF-C significantly promoted cancer cell chemotaxis and invasion without affecting proliferation. However, unlike VEGFA, PDGF-AA and PDGF-C did not affect endothelial cell tube formation or vascular permeability. Interestingly, neutralization of TEC-derived PDGF-C signficantly inhibited tumor cell chemotaxis and invasion, and attenuated EphA2/AKT/P38/ERK signaling in vitro. In vivo, the co-injection of TEC and 4T1 cells resulted in significantly higher primary breast tumor growth and liver metastasis in an orthotopic mouse model.

Conclusion: Our results demonstrate that crosstalk between cancer cells and TEC, partly through angiocrine factors in the TME, induces the rate-limiting steps of metastasis initiation.

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
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信