PO.ET02.09 · 实验与分子治疗
炎性乳腺癌患者来源的外植体：自体乳房切除术后创面液增强与复发和转移相关的黏附组和基质组基因的表达
Inflammatory breast cancer patients derived explants: Autologous post-mastectomy wound fluid enhances the expression of adhesome and matrisome genes associated with recurrence and metastasis
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摘要 Abstract
中文摘要
炎性乳腺癌（IBC）是一种侵袭性表型，全球诊断为IBC的病例正在增加。我们此前的研究表明，构成创伤愈合液的细胞因子组通过诱导与细胞外基质重塑、复发和转移相关的基因表达，促进炎性乳腺癌（IBC）的侵袭性表型。事实上，由于缺乏模型，研究改良根治性乳房切除术后收集的创面引流液是否可能促进IBC复发和癌症干细胞激活受到限制。在此，我们假设新辅助化疗（NACT）后的乳房切除术后创面液（WF）含有诱导复发的生物介质。
方法：本研究纳入50例（31例非IBC；19例IBC）在新辅助化疗后因乳腺癌行乳房切除术的患者。从非IBC和IBC的癌组织及正常乳腺组织生成患者来源的外植体（PDE），以考察将PDE暴露于每位患者收集的自体乳房切除术后WF后基质细胞相关基因和干性相关基因表达的变化。
结果：非IBC正常原发组织的基因表达与IBC相比存在显著差异。IBC癌组织显示E-cadherin基因（CDH1，IBC肿瘤栓子的标志）和基质金属蛋白酶（MMP）显著增加。而与非IBC相比，IBC WF的蛋白质组组成显著富集leptin、PDGF-BB、OSM、angiogenin、IL6、IL8、EGF等。自体IBC WF在正常PDE中增加SPARC、MMP2和MMP3，在癌PDE中增加CDH1、COL6A1、LAMA2、MMP1、MMP3、SELL和THBS3。我们利用了不同的生物信息学工具和应用，如基因本体（GO）和京都基因与基因组百科全书（KEGG），以弥合生物学结果与整体方法之间的差距，从而理解非IBC与IBC疾病生物学之间的差异。研究发现为IBC提供了稳健的分子框架，鉴定出复发的候选生物标志物和潜在的治疗靶点。对表达、相互作用、生存和突变数据的多层验证增强了所检测到的候选基因在IBC生物学中的转化相关性。
查看英文原文 English abstract
Inflammatory breast cancer (IBC) is an aggressive phenotype, cases diagnosed by IBC is increasing worldwide. Our previous study showed that cytokinome composing wound healing fluid contribute to the aggressive phenotype of inflammatory breast cancer (IBC) by inducing expression of genes associated with extracellular matrix remodelling, recurrence and metastasis. Indeed, studying whether wound drainage fluid, collected after modified radial mastectomy may contribute to IBC recurrence and activation of cancer stem cells is limited by the lack of models. Herein, we hypothesized that post-mastectomy wound fluid (WF) after neoadjuvant chemotherapy (NACT) contains biological mediators that induce recurrence.
Methods: Fifty patients (31 non-IBC; 19 IBC) who underwent mastectomy for breast cancer after neoadjuvant chemotherapy were enrolled in the present study. Patient-derived explants (PDEs) were generated from cancer and normal breast tissue of non-IBC and IBC to examine changes in the expression of matricellular- and stemness-related genes after exposing the PDEs to collected autologous postmastectomy-WF for each patient.
Results: Gene expression in non-IBC normal primary tissue was significantly different compared to IBC. The IBC cancer tissues showed a significant increase in E-cadherin gene ( CDH1 ) a hall mark of IBC tumor emboli and Matrix metalloproteinases ( MMP s). While the proteomic composition of IBC WF was significantly enriched for leptin, PDGF-BB, OSM, angiogenin, IL6, IL8, EGF, and others compared to non-IBC. Autologous IBC WF increased SPARC , MMP2, and MMP3 in normal PDEs, and CDH1 , COL6A1 , LAMA2 , MMP1 , MMP3 , SELL , and THBS3 in cancer PDEs. We utilized different bioinformatics tools and applications such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) that bridges the gap between biological results and holistic approach to understand the difference between non-IBC and IBC disease biology. Findings provide a robust molecular framework for IBC, identifying candidate biomarkers for recurrence and potential therapeutic targets. The multi-layer validation of expression, interaction, survival, and mutation data strengthens the translational relevance of the detected candidate genes in IBC biology.
利益披露 Disclosure
M. Mostafa Mohamed, None..
A. Tarek, None..
S. K. El-Sayed, None..
J. Hirshon, None.