在一項(xiàng)研究中，美國州大學(xué)伯克利分校生物工程教授Sanjay Kumar實(shí)驗(yàn)室發(fā)現(xiàn)腫瘤細(xì)胞在體內(nèi)有限空間中能夠遷移得更快,。2012年6月11日,，這篇研究論文在線發(fā)表在PNAS期刊上，共同作者為Sanjay Kumar和博士后研究員Amit Pathak,。
科學(xué)家們知道,，腫瘤對組織的浸潤受到組織機(jī)械性能如硬度和組織微觀結(jié)構(gòu)特性如孔徑大小的調(diào)節(jié)。但是,，過去試圖詳細(xì)地研究和理解這些機(jī)制的努力一直受到限制,，這是因?yàn)槿藗兎浅ｋy以只改變一種性能而不影響其他性能,。
Kumar實(shí)驗(yàn)室利用新開發(fā)的技術(shù)而首次顯示這兩項(xiàng)性能以一種非常不同的方式調(diào)節(jié)腫瘤遷移，而且更令人吃驚的是,，相比于在開放和寬廣的空間中,，細(xì)胞處在有限空間中實(shí)際上能夠讓它們更快速地和更加定向地運(yùn)動。
研究人員已開發(fā)出一種微加工的平臺,，從而能夠構(gòu)建大小和硬度可以獨(dú)立確定的三維通道,。這種結(jié)構(gòu)允許他們更加集中注意力來觀察這些狹窄的通道能夠讓細(xì)胞產(chǎn)生逆著支架方向的牽引力。
Kumar解釋說,，“既然是只有一條路可走,，細(xì)胞會不浪費(fèi)它們的能量來尋找其他的遷移途徑。”
這可能是一種在生理上有著重要作用的機(jī)制,，這是因?yàn)閻盒阅X瘤傾向于沿著組織界面和受限的空間,，如血管和神經(jīng)束，最快速地浸潤組織,。(生物谷 Bioon.com)
doi: 10.1073/pnas.1118073109
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PMID:
Independent regulation of tumor cell migration by matrix stiffness and confinement
Amit Pathak and Sanjay Kumar
Tumor invasion and metastasis are strongly regulated by biophysical interactions between tumor cells and the extracellular matrix (ECM). While the influence of ECM stiffness on cell migration, adhesion, and contractility has been extensively studied in 2D culture, extension of this concept to 3D cultures that more closely resemble tissue has proven challenging, because perturbations that change matrix stiffness often concurrently change cellular confinement. This coupling is particularly problematic given that matrix-imposed steric barriers can regulate invasion speed independent of mechanics. Here we introduce a matrix platform based on microfabrication of channels of defined wall stiffness and geometry that allows independent variation of ECM stiffness and channel width. For a given ECM stiffness, cells confined to narrow channels surprisingly migrate faster than cells in wide channels or on unconstrained 2D surfaces, which we attribute to increased polarization of cell-ECM traction forces. Confinement also enables cells to migrate increasingly rapidly as ECM stiffness rises, in contrast with the biphasic relationship observed on unconfined ECMs. Inhibition of nonmuscle myosin II dissipates this traction polarization and renders the relationship between migration speed and ECM stiffness comparatively insensitive to matrix confinement. We test these hypotheses in silico by devising a multiscale mathematical model that relates cellular force generation to ECM stiffness and geometry, which we show is capable of recapitulating key experimental trends. These studies represent a paradigm for investigating matrix regulation of invasion and demonstrate that matrix confinement alters the relationship between cell migration speed and ECM stiffness.
