Lung-Derived Factors Mediate Breast Cancer Cell Migration through CD44 Receptor-Ligand Interactions in a Novel Ex Vivo System for Analysis of Organ-Specific Soluble Proteins
Lung-Derived Factors Mediate Breast Cancer Cell Migration through CD44 Receptor-Ligand Interactions in a Novel Ex Vivo System for Analysis of Organ-Specific Soluble Proteins
复制标题
DOI：
10.1593/neo.132076
复制
发表时间：
2014-02-01
期刊：
影响因子：
4.8
通讯作者：
Allan, Alison L.
中科院分区：
文献类型：
--
作者：
Chu, Jenny E.;Xia, Ying;Allan, Alison L.
乳腺癌优先转移到肺、淋巴结、肝、骨和脑。然而，目前还不清楚是否癌细胞的性质，器官微环境的性质，或两者的组合是负责这种观察到的器官向性。我们假设乳腺癌细胞在器官微环境中表现出独特的迁移/生长模式，反映了乳腺癌转移的常见临床部位，并且乳腺癌细胞和可溶性器官衍生因子之间的受体-配体相互作用介导了这种行为。使用由器官条件培养基（CM）组成的离体模型系统，人乳腺癌细胞（MDA-MB-231、MDA-MB-468、SUM 149和SUM 159）显示细胞系特异性和器官特异性迁移/增殖模式，其对应于它们的体内转移行为。值得注意的是，暴露于肺-CM增加了所有细胞系的迁移，并增加了四种细胞系中两种的增殖（P <0.05）。通过蛋白芯片技术在肺CM中鉴定了骨桥蛋白（OPN）和L-选择素（SELL）等几种分化簇（CD）44配体。SELL的免疫耗竭降低了MDA-MB-231细胞的迁移，而OPN的耗竭降低了迁移和增殖。用CD 44阻断抗体预处理细胞可消除迁移效应（P <0.05）。具有高醛脱氢酶和CD 44（ALDH（hi）CD 44（+））的“干样”乳腺癌细胞以独特的趋化方式对器官-CM作出反应，优先通过CD 44受体-配体相互作用向肺-CM迁移（P <0.05）。相比之下，ALDH（低）CD 44（-）细胞未观察到迁移的器官特异性变化。我们的数据表明，CD 44（+）乳腺癌细胞和可溶性因子之间的相互作用存在于肺微环境中，可能在决定向器官转移的行为中发挥重要作用。
Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231, MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). "Stemlike" breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDH(hi)CD44(+)) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDH(low)CD44(-) cells. Our data suggest that interactions between CD44(+) breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior.