Quantitative analysis of the effect of cancer invasiveness and collagen concentration on 3D matrix remodeling.
Quantitative analysis of the effect of cancer invasiveness and collagen concentration on 3D matrix remodeling.
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DOI：
10.1371/journal.pone.0024891
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zaman MH
中科院分区：
文献类型：
--
作者：
Harjanto D;Maffei JS;Zaman MH
细胞外基质（ECM）重塑是细胞迁移和肿瘤转移的关键组成部分，并与癌症进展有关。尽管基质重塑的重要性，系统的和定量的研究在很大程度上是缺乏的过程。此外，它仍然不清楚，如果破坏紧张的稳态特征的恶性肿瘤是由于最初改变ECM和组织的性质，或改变组织的肿瘤细胞。为了探索这些问题，我们研究了两种不同的前列腺癌细胞系在三维胶原蛋白系统中的基质重塑。在一周内，我们监测不同胶原蛋白含量的凝胶的结构变化，使用共聚焦反射显微镜和定量图像分析，跟踪指标的原纤维分数，孔径，纤维长度和直径。定量比较没有接种细胞（对照）、LNCaP细胞和DU-145细胞的凝胶。如预期的，具有较高胶原蛋白含量的凝胶最初具有较小的孔径和较高的原纤维分数。然而，随着时间的推移，LNCaP-和DU-145-填充的基质显示出彼此之间以及与对照凝胶相比不同的结构特性，LNCaP细胞似乎比DU-145细胞更有利于具有较低胶原纤维分数和较大孔的微环境。我们认为DU-145细胞对致密基质的偏好是由于其较高的侵袭力和蛋白水解能力。基质蛋白酶的抑制导致高浓度凝胶接种任一细胞类型的原纤维部分减少，支持我们的假设。我们的新的定量结果探测凝胶重塑的动力学在三个维度，并建议前列腺癌细胞重塑其ECM的协同方式，这是依赖于初始基质的属性，以及他们的侵袭性。
Extracellular matrix (ECM) remodeling is a key component of cell migration and tumor metastasis, and has been associated with cancer progression. Despite the importance of matrix remodeling, systematic and quantitative studies on the process have largely been lacking. Furthermore, it remains unclear if the disrupted tensional homeostasis characteristic of malignancy is due to initially altered ECM and tissue properties, or to the alteration of the tissue by tumor cells. To explore these questions, we studied matrix remodeling by two different prostate cancer cell lines in a three-dimensional collagen system. Over one week, we monitored structural changes in gels of varying collagen content using confocal reflection microscopy and quantitative image analysis, tracking metrics of fibril fraction, pore size, and fiber length and diameter. Gels that were seeded with no cells (control), LNCaP cells, and DU-145 cells were quantitatively compared. Gels with higher collagen content initially had smaller pore sizes and higher fibril fractions, as expected. However, over time, LNCaP- and DU-145-populated matrices showed different structural properties compared both to each other and to the control gels, with LNCaP cells appearing to favor microenvironments with lower collagen fiber fractions and larger pores than DU-145 cells. We posit that the DU-145 cells' preference for denser matrices is due to their higher invasiveness and proteolytic capabilities. Inhibition of matrix proteases resulted in reduced fibril fractions for high concentration gels seeded with either cell type, supporting our hypothesis. Our novel quantitative results probe the dynamics of gel remodeling in three dimensions and suggest that prostate cancer cells remodel their ECM in a synergistic manner that is dependent on both initial matrix properties as well as their invasiveness.