PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2024-08-08 DOI:10.1007/s10456-024-09941-9
Die Yu, Hanzheng Xu, Jinzhe Zhou, Kai Fang, Zekun Zhao, Ke Xu
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Abstract

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

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PDPN/CCL2/STAT3反馈回路改变CAF异质性,促进结直肠癌血管生成。
结直肠癌(CRC)是常见的临床恶性肿瘤之一,也是全球第四大癌症相关死亡原因。肿瘤微环境(TME)在促进肿瘤血管生成方面起着至关重要的作用,而癌相关成纤维细胞(CAFs)是肿瘤微环境的关键组成部分之一。然而,由于CAFs的高度异质性,阐明CAF介导肿瘤血管生成的分子机制仍是一个难题。在我们的研究中,我们发现结直肠癌中的CAFs存在促血管生成功能异质性,并明确了Podoplanin(PDPN)可特异性标记具有促血管生成功能的CAF亚群。我们还发现,PDPN + CAF 可通过自分泌的 CCL2 形成 PDPN/CCL2/STAT3 反馈环,从而维持 CAF 的异质性,同时通过旁分泌的 CCL2 激活内皮细胞中的 STAT3 信号通路,促进血管生成。我们的研究表明,WP1066可通过阻断CAFs中的PDPN/CCL2/STAT3反馈环和内皮细胞中的STAT3信号通路抑制结直肠癌血管生成。总之,我们的研究表明,STAT3 可能是阻断结直肠癌血管生成的潜在治疗靶点。我们的研究为结直肠癌的临床治疗提供了理论依据和新的治疗策略。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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