Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion.
Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion.
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DOI：
10.1158/0008-5472.can-11-1818
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发表时间：
2011-11-01
期刊：
影响因子：
11.2
通讯作者：
Pearson GW
中科院分区：
文献类型：
--
作者：
Dang TT;Prechtl AM;Pearson GW
大多数导管性乳腺癌细胞在体外和体内均具有弱侵袭性，这表明其微环境的成分可能促进其在进展过程中从原位过渡到侵袭阶段。在这里，我们报道了乳腺成纤维细胞的共同培养通过一种与配体无关的机制特异性地触发基底型乳腺癌细胞的侵袭行为。当在器官型培养中单独培养时，基底型和发光型乳腺癌细胞均形成具有导管原位癌（DCIS）特征的非侵入性球体。相比之下，当与乳腺成纤维细胞共培养时，基底型球状体表现出侵袭性特征，而光型球状体则保留了良性和非侵入性的导管样结构。实时成像和功能研究显示，侵袭的特异性与基底型乳腺癌细胞在球体内移动的独特能力有关。乳腺成纤维细胞通过触发基底型乳腺癌细胞从乳腺上皮形态形成的非侵入性程序转化为萌发内皮血管生成的侵入性程序来诱导侵袭。与现有的入侵模型相反，成纤维细胞产生的可溶性配体不足以触发入侵。相反，基底型侵袭依赖于成纤维细胞对细胞外基质中胶原纤维的cdc42依赖性重组。用临床相关药物抑制基底型细胞运动在器官型培养和动物中阻断了侵袭，为早期患者提供了一种新的治疗策略。总之，我们的研究结果表明，基底型乳腺癌细胞向早期肿瘤募集成纤维细胞足以触发其从良性、非侵袭性dcis样阶段向恶性侵袭阶段的转变。此外，我们的研究结果表明，不同亚型的乳腺癌可能需要微环境的不同类型的贡献才能发生恶性进展。
Most ductal breast carcinoma cells are weakly invasive in vitro and in vivo, suggesting that components of their microenvironment may facilitate a transition from in situ to invasive stages during progression. Here we report that co-culture of mammary fibroblasts specifically triggers invasive behavior in basal-type breast cancer cells through a ligand independent mechanism. When cultured alone in organotypic culture, both basal and luminal-type breast cancer cells formed noninvasive spheroids with characteristics of ductal carcinoma in situ (DCIS). In contrast, when co-cultured with mammary fibroblasts, basal-type spheroids exhibited invasive character whereas the luminal-type spheroids retained a benign and noninvasive duct-like architecture. Real-time imaging and functional studies revealed that the specificity of invasion was linked to a unique capacity of basal-type breast cancer cells to move within spheroids. Mammary fibroblasts induced invasion by triggering basal-type breast cancer cells to convert from a noninvasive program of mammary epithelial morphogenesis, to an invasive program of sprouting endothelial angiogenesis. Contrary to existing invasion models, soluble ligands produced by the fibroblasts were not sufficient to trigger invasion. Instead, basal-type invasion relied upon a Cdc42-dependent reorganization of collagen fibers in the extracellular matrix by fibroblasts. Inhibiting basal-type cell movement with clinically relevant drugs blocked invasion in organotypic culture and in animals, suggesting a new treatment strategy for early-stage patients. Together our findings establish that fibroblast recruitment by basal-type breast cancer cells into early-stage tumors is sufficient to trigger their conversion from a benign, non-invasive DCIS-like stage to a malignant invasive stage. Further, our findings suggest that different subtypes of breast cancer may require distinct types of contributions from the microenvironment to undergo malignant progression.