Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
Cancer Prev Res (Phila). 2017 Sep;10(9):514-524. doi: 10.1158/1940-6207.CAPR-16-0335. Epub 2017 Jul 28.
Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of "metastatic inefficiency." Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. .
肺癌被证实具有显著的肿瘤内遗传异质性。然而，对于生物物理特性（如细胞迁移）的异质性及其与早期疾病发病机制和微转移播散的关系，人们知之甚少。在这项研究中，我们鉴定并选择了一小部分具有高迁移能力的癌前气道上皮细胞亚群，这些细胞能够以未选择的永生化上皮细胞系的 100 倍以上的速度通过微尺度的收缩。这种增强的迁移能力被证明是 Rac1 依赖性和可遗传的，因为在选择后超过 8 周的多次细胞分裂中维持了表型。这个肺上皮亚群的形态学特征是细胞突起强度增加。在一个微转移播种和肺定植的小鼠模型中，经过迁移选择的癌前细胞在短期测定中表现出更强的存活能力，并且在长期测定中表现出癌前病变的生长增强，从而克服了“转移效率低下”的重要方面。总的来说，我们的研究结果表明，在永生化的癌前气道上皮细胞系中，存在具有遗传迁移相关生物物理特性的亚群，这些亚群可能解释了肺癌发病早期的微转移播种现象。了解、靶向和预防这些关键的生物物理特征及其潜在的分子机制，可能为预防转移行为提供一种新的方法。
