Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells
Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells
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DOI：
10.1186/s12885-019-5521-8
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发表时间：
2019-04-04
期刊：
影响因子：
3.8
通讯作者：
Buess, Martin
中科院分区：
文献类型：
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作者：
Ferraro, Daniela A.;Patella, Francesca;Buess, Martin
背景：肿瘤微环境是恶性肿瘤进展的关键调节因子。虽然内皮细胞在肿瘤血管生成的背景下已被广泛研究，但其作为癌细胞侵袭和迁移的调节剂的作用知之甚少。方法：我们研究了内皮细胞对体外人癌细胞侵袭和迁移行为的影响。结果：在暴露于内皮细胞的培养上清液后，不同的癌细胞，如SK-BR-3细胞，显示显著增加的侵袭和细胞迁移，伴随着细胞形态和基因表达的变化，使人联想到上皮-间充质转化（EMT）。有趣的是，SK-BR-3细胞的促迁移作用显着增强从亚融合，增殖的内皮细胞，而不是从融合，静止的内皮细胞获得的上清液。通过定量MS蛋白质组学系统地比较亚融合和融合内皮细胞的上清液，揭示了8种候选蛋白，其由融合内皮细胞以显著更高的水平分泌，代表癌细胞迁移的潜在抑制剂。在这些蛋白质中，巢蛋白-1仅在融合的内皮细胞中表达，并且被发现对于抑制SK-BR-3细胞迁移是必要且充分的。事实上，SK-BR-3细胞暴露于巢蛋白-1耗尽的内皮上清液显示出增加的前迁移STAT 3磷酸化沿着增加的细胞迁移。这反映了增强SK-BR-3迁移的情况下，刺激与条件培养基从亚融合内皮细胞与固有的nidogen-1 expression.Conclusion的情况：nidogen-1作为内皮衍生的抑制剂的迁移不同的癌细胞类型的鉴定揭示了一种新的机制，内皮细胞控制癌症的进展。
Background: The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood.Methods: We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro.Results: Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression.Conclusion: The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.