转移性卵巢癌中观察到的胶原纤维密度促进肿瘤细胞粘附。

Ali Abbaspour, Ana L Martinez Cavazos, Roshan Patel, Ning Yang, Stephanie M McGregor, Erin G Brooks, Kristyn S Masters, Pamela K Kreeger
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引用次数: 0

摘要

I型胶原是细胞外基质(ECM)的关键结构成分,在癌症中经常发生改变,原发肿瘤部位纤维组织的改变与转移和不良患者预后有关。在这里,我们证明胶原纤维在转移部位,如高级别浆液性卵巢癌(HGSOC)患者的网膜中也发生了改变。具体来说,我们观察到纤维密度、排列和宽度显著增加。为了确定纤维密度的增加是否支持转移,我们使用了半互穿的甲基丙烯酸凝胶(gelMA)网络与增加的纤维胶原蛋白结合使用。随着胶原纤维密度的增加,癌细胞黏附性明显增加。为了确定起作用的机制,我们使用正交系统研究了1)暴露在胶原蛋白(GFOGER)和明胶(RGD)中的不同粘附肽,以及2)纤维的物理结构。无论是单独使用GFOGER还是与RGD联合使用,细胞对GFOGER的反应都很小,这表明黏附的增加不是由这种胶原特异性相互作用引起的。与扁平的聚氯乙烯-明胶基质相比,静电纺聚氯乙烯-明胶纤维上的细胞粘附性显著提高,这表明细胞粘附性的增加是由纤维结构引起的。接下来,我们研究了参与gelMA/coll黏附增加的细胞机制,发现需要肌动蛋白聚合,而不是肌球蛋白II收缩。我们进一步证明纤维凝胶上的细胞具有更强的肌动蛋白聚合,这导致了更大的粘附强度。综上所述,这些结果表明,肿瘤转移时胶原纤维的增加将支持其他转移的发展。意义声明:本研究通过描述胶原纤维如何随疾病进展而变化,推进了对晚期卵巢癌中最常见的转移部位——网膜基质的评估。为了研究胶原纤维对转移的影响,我们利用一套体外生物材料来确定胶原纤维在支持细胞粘附方面的新作用,通过在新生粘附形成过程中增加肌动蛋白动力学,从而导致后期粘附强度增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Collagen fiber density observed in metastatic ovarian cancer promotes tumor cell adhesion.

Collagen type I, a key structural component of the extracellular matrix (ECM), is frequently altered in cancer, with altered fiber organization at the primary tumor site linked to metastasis and poor patient outcomes. Here, we demonstrate that collagen fibers are also altered in metastatic sites such as the omentum of patients with high-grade serous ovarian cancer (HGSOC). Specifically, we observed a significant increase in fiber density, alignment, and width. To determine if the increase in fiber density supports metastasis, we used a semi-interpenetrating methacrylated gelatin (gelMA) network in combination with increasing fibrillar collagen. Cancer cells had significantly increased adhesion as collagen fiber density increased. To determine the responsible mechanisms, we used orthogonal systems to examine 1) the different adhesion peptides exposed in collagen (GFOGER) and gelatin (RGD), and 2) the physical structure of fibers. Cells had minimal response to GFOGER, either alone or in combination with RGD, suggesting that increased adhesion did not result from this collagen-specific interaction. Cell adhesion was significantly higher on electrospun PCL-gelatin fibers compared to flat PCL-gelatin substrates, suggesting that increased cell adhesion resulted from fiber structure. We next investigated the cellular mechanisms involved in increased adhesion on gelMA/coll and found that actin polymerization, but not myosin II contractility, was needed. We further demonstrated that cells on fibrous gels had more robust actin polymerization, and that this resulted in greater adhesion strength. Combined, these results suggest that the increase in collagen fibers with tumor metastasis will support the development of additional metastases. STATEMENT OF SIGNIFICANCE: This work advances the evaluation of the matrisome of the omentum, the most common metastatic site in advanced ovarian cancer by characterizing how collagen fibers change with disease progression. To examine the effect of collagen fibers on metastasis, we utilized a suite of in vitro biomaterials to identify a novel role for collagen fibers in supporting cell adhesion through increased actin dynamics during nascent adhesion formation, which results in increased adhesion strength at later times.

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