Abstract:
A basic process in cancer is the breaching of basement-membrane barriers to permit tissue invasion. Cancer cells can use proteases and physical mechanisms to produce initial holes in basement membranes, but how cells squeeze through this barrier into matrix environments is not well understood. We used a 3D invasion model consisting of cancer-cell spheroids encapsulated by a basement membrane and embedded in collagen to characterize the dynamic early steps in cancer-cell invasion across this barrier. We demonstrate that certain cancer cells extend exceptionally long (~30-100 μm) protrusions through basement membranes via actin and microtubule cytoskeletal function. These long protrusions use integrin adhesion and myosin II-based contractility to pull cells through the basement membrane for initial invasion. Concurrently, these long, organelle-rich protrusions pull surrounding collagen inward while propelling cancer cells outward through perforations in the basement-membrane barrier. These exceptionally long, contractile cellular protrusions can facilitate the breaching of the basement-membrane barrier as a first step in cancer metastasis.
摘要:
癌症的基本过程是破坏基底膜屏障以允许组织侵入。癌细胞可以利用蛋白酶和物理机制在基底膜上产生初始孔,但是细胞如何通过这个屏障挤入基质环境还没有很好的理解。我们使用了3D侵袭模型,该模型由被基底膜包裹并嵌入胶原蛋白中的癌细胞球体组成,以表征癌细胞侵入该屏障的动态早期步骤。我们证明某些癌细胞通过肌动蛋白和微管细胞骨架功能通过基底膜延伸异常长(〜30-100μm)的突起。这些长突起利用整联蛋白粘附和基于肌球蛋白II的收缩性来拉动细胞通过基底膜进行初始入侵。同时,这些长,富含细胞器的突起向内拉动周围的胶原蛋白,同时通过基底膜屏障中的穿孔向外推动癌细胞。这些异常长,作为癌症转移的第一步,收缩性细胞突起可以促进基底膜屏障的破坏。