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Obesity-Associated Adipose Stromal Cells Promote Breast Cancer Invasion through Direct Cell Contact and ECM Remodeling

机译:肥胖相关的脂肪糖分子细胞通过直接细胞接触和ECM重塑促进乳腺癌侵袭

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摘要

Obesity increases the risk and worsens the prognosis for breast cancer due, in part, to altered adipose stromal cell (ASC) behavior. Whether ASCs from obese individuals increase migration of breast cancer cells relative to their lean counterparts, however, remains unclear. To test this connection, multicellular spheroids composed of MCF10A-derived tumor cell lines of varying malignant potential and lean or obese ASCs are embedded into collagen scaffolds mimicking the elastic moduli of interstitial breast adipose tissue. Confocal image analysis suggests that tumor cells alone migrate insignificantly under these conditions. However, direct cell-cell contact with either lean or obese ASCs enables them to migrate collectively, whereby obese ASCs activate tumor cell migration more effectively than their lean counterparts. Time-resolved optical coherence tomography imaging suggests that obese ASCs facilitate tumor cell migration by mediating contraction of local collagen fibers. Matrix metalloproteinase (MMP)-dependent proteolytic activity significantly contributes to ASC-mediated tumor cell invasion and collagen deformation. However, ASC contractility is also important, as co-inhibition of both MMPs and contractility is necessary to completely abrogate ASC-mediated tumor cell migration. These findings imply that obesity-mediated changes of ASC phenotype may impact tumor cell migration and invasion with potential implications for breast cancer malignancy in obese patients.
机译:肥胖增加了风险,部分地增加了乳腺癌的预后,部分地改变了脂肪瘤的基质细胞(ASC)行为。然而,来自肥胖个体的ASC是否增加了乳腺癌细胞相对于瘦患者的迁移,但仍然尚不清楚。为了测试这一连接,由不同恶性潜力和瘦或肥胖的肿瘤细胞系的MCF10A衍生的肿瘤细胞系组成的多细胞球体嵌入到模仿中性乳腺脂肪组织的弹性模量的胶原蛋白支架中。共聚焦图像分析表明,在这些条件下单独迁移肿瘤细胞。然而,与瘦或肥胖ASC的直接细胞 - 细胞接触使它们能够集体迁移,从而更有效地激活肿瘤细胞迁移,而不是它们的瘦对应物。时间分辨光学相干断层摄影成像表明,肥胖ASCS通过介导局部胶原纤维的收缩来促进肿瘤细胞迁移。基质金属蛋白酶(MMP) - 依赖性蛋白水解活性显着有助于ASC介导的肿瘤细胞侵袭和胶原变形。然而,ASC收缩性也很重要,因为必须为MMP和收缩性的共同抑制完全消除ASC介导的肿瘤细胞迁移。这些发现意味着肥胖介导的ASC表型的变化可能会影响肿瘤细胞迁移和侵袭肥胖患者对乳腺癌恶性肿瘤的潜在影响。

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  • 来源
    《Advanced Functional Materials》 |2020年第48期|1910650.1-1910650.13|共13页
  • 作者单位

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA|Cornell Univ Sch Elect & Comp Engn Ithaca NY 14853 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA;

    Cornell Univ Inst Biotechnol Ithaca NY 14853 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10021 USA|Icahn Sch Med Mt Sinai Dept Oncol Sci New York NY 10029 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA|Weill Cornell Med Div Plast Surg New York NY 10021 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA;

    Cornell Univ Nancy E & Peter C Meinig Sch Biomed Engn Ithaca NY 14853 USA|Cornell Univ Kavli Inst Cornell Nanoscale Sci Ithaca NY 14853 USA;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    collagen; extracellular matrix remodeling; obesity; optical coherence tomography; tumor invasion;

    机译:胶原蛋白;细胞外基质重塑;肥胖;光学相干断层扫描;肿瘤入侵;

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