Department of Bioengineering, Northeastern University, Boston, MA, USA.
Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA.
FASEB J. 2020 May;34(5):6166-6184. doi: 10.1096/fj.201901920R. Epub 2020 Mar 13.
Cancer metastasis and secondary tumor initiation largely depend on circulating tumor cell (CTC) and vascular endothelial cell (EC) interactions by incompletely understood mechanisms. Endothelial glycocalyx (GCX) dysfunction may play a significant role in this process. GCX structure depends on vascular flow patterns, which are irregular in tumor environments. This work presents evidence that disturbed flow (DF) induces GCX degradation, leading to CTC homing to the endothelium, a first step in secondary tumor formation. A 2-fold greater attachment of CTCs to human ECs was found to occur under DF conditions, compared to uniform flow (UF) conditions. These results corresponded to an approximately 50% decrease in wheat germ agglutinin (WGA)-labeled components of the GCX under DF conditions, vs UF conditions, with undifferentiated levels of CTC-recruiting E-selectin under DF vs UF conditions. Confirming the role of the GCX, neuraminidase induced the degradation of WGA-labeled GCX under UF cell culture conditions or in Balb/C mice and led to an over 2-fold increase in CTC attachment to ECs or Balb/C mouse lungs, respectively, compared to untreated conditions. These experiments confirm that flow-induced GCX degradation can enable metastatic CTC arrest. This work, therefore, provides new insight into pathways of secondary tumor formation.
癌症转移和继发性肿瘤的发生在很大程度上取决于循环肿瘤细胞（CTC）和血管内皮细胞（EC）之间的相互作用，但这种相互作用的机制尚不完全清楚。内皮糖萼（GCX）功能障碍可能在这个过程中起重要作用。GCX 的结构取决于血管内的流动模式，而肿瘤环境中的流动模式是不规则的。本研究证明，紊乱的流动（DF）会导致 GCX 降解，从而促使 CTC 归巢到内皮细胞，这是继发性肿瘤形成的第一步。与均匀流动（UF）条件相比，发现 CTC 在 DF 条件下与人类 EC 的附着增加了 2 倍。这些结果与 DF 条件下 WGA 标记的 GCX 成分比 UF 条件下减少了约 50%相对应，而在 DF 条件下与 UF 条件下相比，募集 CTC 的 E-选择素的未分化水平相同。证实了 GCX 的作用，神经氨酸酶在 UF 细胞培养条件下或在 Balb/C 小鼠中诱导 WGA 标记的 GCX 降解，与未处理条件相比，分别导致 CTC 与 EC 或 Balb/C 小鼠肺的附着增加了 2 倍以上。这些实验证实，流动诱导的 GCX 降解可以使转移性 CTC 停滞。因此，这项工作为继发性肿瘤形成的途径提供了新的见解。
