Tumor and Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Neoplasia. 2012 Mar;14(3):249-58. doi: 10.1593/neo.111498.
The complexity of the process of metastasis is widely recognized. We report herein on a recurrent feature of high compared to low metastatic cells that is linked to their ability to survive early after their arrival at secondary sites. Using novel fluorescent-based imaging strategies that assess tumor cell interaction with the lung microenvironment, we have determined that most high and low metastatic cells can be distinguished within 6 hours of their arrival in the lung and further that this difference is defined by the ability of high metastatic cells to resist apoptosis at the secondary site. Despite the complexity of the metastatic cascade, the performance of cells during this critical window is highly defining of their metastatic proclivity. To explore mechanisms, we next evaluated biochemical pathways that may be linked to this survival phenotype in highly metastatic cells. Interestingly, we found no association between the Akt survival pathway and this metastatic phenotype. Of all pathways examined, only protein kinase C (PKC) activation was significantly linked to survival of highly metastatic cells. These data provide a conceptual understanding of a defining difference between high and low metastatic cells. The connection to PKC activation may provide a biologic rationale for the use of PKC inhibition in the prevention of metastatic progression.
转移过程的复杂性是众所周知的。我们在此报告一个与高转移性细胞相关的反复出现的特征，该特征与它们在到达次级部位后早期存活的能力有关。我们使用新型荧光成像策略评估肿瘤细胞与肺部微环境的相互作用，确定在到达肺部后的 6 小时内可以区分大多数高转移性和低转移性细胞，并且这种差异是由高转移性细胞在次级部位抵抗细胞凋亡的能力决定的。尽管转移级联反应非常复杂，但细胞在这个关键窗口期的表现高度决定了它们的转移倾向。为了探索机制，我们接下来评估了可能与高转移性细胞这种存活表型相关的生化途径。有趣的是，我们没有发现 Akt 存活途径与这种转移表型之间存在关联。在所有检查的途径中，只有蛋白激酶 C（PKC）的激活与高转移性细胞的存活显著相关。这些数据提供了一个概念性的理解，即在高转移性和低转移性细胞之间存在一个决定性的差异。与 PKC 激活的联系可能为使用 PKC 抑制来预防转移进展提供了生物学依据。
