Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America.
PLoS One. 2013;8(1):e54959. doi: 10.1371/journal.pone.0054959. Epub 2013 Jan 23.
Hematogeneous metastasis can occur via a cascade of circulating tumor cell adhesion events to the endothelial lining of the vasculature, i.e. the metastatic cascade. Interestingly, the pro-inflammatory cytokines IL-6 and TNF-α, which play an important role in potentiating the inflammatory cascade, are significantly elevated in metastatic breast cancer (BCa) patients. Despite their high metastatic potential, human breast carcinoma cells MDA-MB-231 lack interactions with E-selectin functionalized surfaces under physiological shear stresses. We hypothesized that human plasma, 3-D tumor spheroid culture, and cytokine-supplemented culture media could induce a phenotypic switch that allows BCa cells to interact with E-selectin coated surfaces under physiological flow. Flow cytometry, immunofluorescence imaging, and flow-based cell adhesion assay were utilized to investigate the phenotypic changes of MDA-MB-231 cells with various treatments. Our results indicate that plasma, IL-6, and TNF-α promote breast cancer cell growth as aggregates and induce adhesive recruitment of BCa cells on E-selectin coated surfaces under flow. 3-D tumor spheroid culture exhibits the most significant increases in the interactions between BCa and E-selectin coated surfaces by upregulating CD44V4 and sLe(x) expression. Furthermore, we show that IL-6 and TNF-α concentrations in blood may regulate the recruitment of BCa cells to the inflamed endothelium. Finally, we propose a mechanism that could explain the invasiveness of 'triple-negative' breast cancer cell line MDA-MB-231 via a positive feedback loop of IL-6 secretion and maintenance. Taken together, our results suggest that therapeutic approaches targeting cytokine receptors and adhesion molecules on cancer cells may potentially reduce metastatic load and improve current cancer treatments.
血源性转移可通过一系列循环肿瘤细胞与血管内皮的黏附事件发生，即转移级联。有趣的是，在转移性乳腺癌（BCa）患者中，促炎细胞因子 IL-6 和 TNF-α 显著升高，它们在增强炎症级联反应中发挥着重要作用。尽管具有很高的转移潜力，但人类乳腺癌细胞 MDA-MB-231 在生理剪切应力下与 E-选择素功能化表面缺乏相互作用。我们假设人血浆、3-D 肿瘤球体培养和细胞因子补充培养基可以诱导表型转换，使 BCa 细胞在生理流动下与 E-选择素涂层表面相互作用。我们利用流式细胞术、免疫荧光成像和基于流动的细胞黏附测定法研究了不同处理方式下 MDA-MB-231 细胞的表型变化。结果表明，血浆、IL-6 和 TNF-α 促进乳腺癌细胞以聚集体的形式生长，并在流动下诱导 BCa 细胞在 E-选择素涂层表面的黏附募集。3-D 肿瘤球体培养通过上调 CD44V4 和 sLe(x) 表达，显著增加了 BCa 与 E-选择素涂层表面之间的相互作用。此外，我们表明血液中的 IL-6 和 TNF-α 浓度可能调节 BCa 细胞向炎症内皮的募集。最后，我们提出了一个机制，该机制可以解释 IL-6 分泌和维持的正反馈环如何使“三阴性”乳腺癌细胞系 MDA-MB-231 具有侵袭性。总之，我们的结果表明，针对癌细胞上细胞因子受体和黏附分子的治疗方法可能有助于降低转移负荷并改善当前的癌症治疗方法。
