蛋白质组学分析鉴定基质TGF-β1/podoplanin轴是结直肠癌进展的驱动因素。

IF 12.8 1区 医学 Q1 ONCOLOGY
Silvia Di Agostino, Davide La Padula, Vittoria Rago, Caterina Gabriele, Francesco Conforti, Elio Aprigliano, Lidia Urlandini, Elvira Parrotta, Danilo Lofaro, Francesca Vescio, Andrea Sacconi, Valeria Cernaro, Giuseppe Currò, Angela Alibrandi, Girolamo Ranieri, Valeria Zuccalà, Antonio Ieni, Marco Gaspari, Giovanni Cuda, Michele Ammendola, Vittorio Abbonante
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引用次数: 0

摘要

背景:肿瘤微环境(tumor microenvironment, TME)在结直肠癌(colorectal cancer, CRC)的发生发展中起着关键作用,但其组成部分之间的复杂串扰尚未完全了解。癌症相关成纤维细胞(CAFs)和肿瘤相关巨噬细胞(tam)已成为结直肠癌进展的关键调节因子,但它们的具体作用,特别是考虑到它们的异质性,尚未完全阐明。本研究确定了podoplanin (PDPN),一种富集于CAFs中的跨膜糖蛋白,在结直肠癌TME中高度表达,特别是在肿瘤周围,并与巨噬细胞浸润和癌症进展相关。方法:我们对患者匹配的结直肠癌和邻近的正常组织进行了基于质谱的蛋白质组学分析,以确定改变的信号通路和蛋白质表达。通过免疫组织化学和免疫荧光分析,评估了来自两个独立队列的结直肠癌样本中PDPN表达的临床相关性。我们分析了基因表达综合数据库(Gene Expression Omnibus, GEO)的公开数据,以评估PDPN表达与患者生存之间的关系。利用直接和间接共培养系统研究巨噬细胞浸润对间质PDPN表达的影响及其对结肠腺癌细胞生长的影响。结果:PDPN在结直肠肿瘤组织间质中的表达较正常组织明显升高,且与m2样巨噬细胞浸润相关。高PDPN表达与CRC患者无复发生存率降低相关。m2样巨噬细胞预处理的基质细胞上调PDPN,更有效地支持三种结肠腺癌细胞系的生长。PDPN缺失损害了基质细胞促进肿瘤细胞增殖的能力。在机制上,m2样巨噬细胞预处理诱导TGF-β1依赖性的YAP/TAZ核定位、RhoA/ROCK/肌球蛋白驱动的细胞骨架收缩性和基质细胞外基质(ECM)产生的增加。抑制TGF-β1信号或ROCK活性可减少基质对癌细胞生长的支持。结论:本研究揭示了TME促进结直肠癌进展的新机制,并强调了PDPN作为结直肠癌潜在的预后生物标志物和治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.

Background: The tumor microenvironment (TME) plays a pivotal role in the development and progression of colorectal cancer (CRC), yet the complex crosstalk among its components remains incompletely understood. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) have emerged as key regulators of CRC progression, but their specific contributions, particularly given their heterogeneity, are not fully elucidated. This study identifies podoplanin (PDPN), a transmembrane glycoprotein enriched in CAFs, as highly expressed in the CRC TME, in particular surrounding the tumor, and associated with macrophage infiltration and cancer progression.

Methods: We performed mass spectrometry-based proteomic analysis on matched CRC and adjacent normal tissues from patients to identify altered signaling pathways and protein expression. The clinical relevance of PDPN expression was evaluated in CRC samples from two independent cohorts using immunohistochemistry and immunofluorescence analysis. Publicly available data from the Gene Expression Omnibus (GEO) database were analyzed to assess the association between PDPN expression and patient survival. Functional assays using direct and indirect co-culture systems investigated the influence of macrophage infiltration on stromal PDPN expression and its effect on colon adenocarcinoma cell growth.

Results: PDPN expression was significantly elevated in the stroma of the colorectal tumor tissues compared to normal tissues and correlated with M2-like macrophage infiltration. High PDPN expression was associated with reduced relapse-free survival in CRC patients. Stromal cells pre-conditioned with M2-like macrophages upregulated PDPN and more effectively supported the growth of three colon adenocarcinoma cell lines. PDPN depletion impaired the ability of stromal cells to promote tumor cell proliferation. Mechanistically, M2-like macrophage pre-conditioning induced a TGF-β1-dependent increase in YAP/TAZ nuclear localization, RhoA/ROCK/myosin-driven cytoskeletal contractility, and extracellular matrix (ECM) production in stromal cells. Inhibition of TGF-β1 signaling or ROCK activity reduced stromal support for cancer cell growth.

Conclusion: This study reveals a novel mechanism by which the TME facilitates CRC progression and highlights PDPN as a potential prognostic biomarker and therapeutic target in CRC.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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