Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche.
Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche.
复制标题
转移性细胞定植的细胞外基质介质，使用脚手架模拟物的脚手裂。
DOI：
10.1016/j.actbio.2016.01.043
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发表时间：
2016-03
影响因子：
9.7
通讯作者：
Shea LD
中科院分区：
文献类型：
--
作者：
Aguado BA;Caffe JR;Nanavati D;Rao SS;Bushnell GG;Azarin SM;Shea LD
转移性肿瘤细胞定植于转移前生态位，这是一个复杂的微环境，部分由细胞外基质（ECM）蛋白组成。我们试图用ECM包被聚（ε-己内酯）（PCL）支架作为转移前生态位的模拟物来识别和验证肿瘤细胞定植的新贡献者。利用原位乳腺癌小鼠模型，植入皮下间隙的纤维连接蛋白和胶原iv包被支架捕获了定植的肿瘤细胞，与未包被支架相比，植入部位的肿瘤细胞积累增加了2倍以上。作为鉴定其他ECM定植贡献者的策略，对肺和肝脏中含有转移性肿瘤的去细胞化基质（DCM）进行了表征。在体外，相对于健康的DCM，病变器官的DCM涂层上的转移细胞粘附增加。此外，与健康的DCM涂层相比，患病DCM涂层支架的体内植入增加了肿瘤细胞的定植。对健康和患病DCM进行质谱蛋白质组学分析，以确定与定植相关的候选DCM。髓过氧化物酶被鉴定为大量存在于病变器官中，并被证实是髓过氧化物酶涂层支架植入物定植的一个贡献者。这项工作使用脱细胞和蛋白质组学技术鉴定了与定植相关的新型ECM蛋白，并使用支架模拟转移前生态位验证了候选蛋白。
Metastatic tumor cells colonize the pre-metastatic niche, which is a complex microenvironment consisting partially of extracellular matrix (ECM) proteins. We sought to identify and validate novel contributors to tumor cell colonization using ECM coated poly(ε-caprolactone) (PCL) scaffolds as mimics of the pre-metastatic niche. Utilizing orthotopic breast cancer mouse models, fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space captured colonizing tumor cells, showing a greater than 2-fold increase in tumor cell accumulation at the implant site compared to uncoated scaffolds. As a strategy to identify additional ECM colonization contributors, decellularized matrix (DCM) from lungs and livers containing metastatic tumors were characterized. In vitro, metastatic cell adhesion was increased on DCM coatings from diseased organs relative to healthy DCM. Furthermore, in vivo implantations of diseased DCM-coated scaffolds had increased tumor cell colonization relative to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy and diseased DCM to identify candidates associated with colonization. Myeloperoxidase was identified as abundantly present in diseased organs and validated as a contributor to colonization using myeloperoxidase-coated scaffold implants. This work identified novel ECM proteins associated with colonization using decellularization and proteomics techniques and validated candidates using a scaffold to mimic the pre-metastatic niche.