Dynamic interactions between cancer cells and the embryonic microenvironment regulate cell invasion and reveal EphB6 as a metastasis suppressor.
Dynamic interactions between cancer cells and the embryonic microenvironment regulate cell invasion and reveal EphB6 as a metastasis suppressor.
复制标题
DOI：
10.1158/1541-7786.mcr-13-0673
复制
发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Kulesa PM
中科院分区：
文献类型：
--
作者：
Bailey CM;Kulesa PM
转移性扩散导致黑色素瘤的高死亡率。然而，在转移侵袭过程中对体内细胞动态可视化的局限性限制了我们对这些细胞行为的理解。近期的证据表明，黑色素瘤细胞利用其祖先胚胎神经嵴迁移程序的部分来促进侵袭。有待确定的是胚胎微环境信号如何影响侵袭性黑色素瘤细胞的行为，以及这些信号是否与人类疾病相关。为了解决这些问题，我们利用双光子延时显微镜研究了神经嵴微环境在决定鸡胚中黑色素瘤细胞侵袭的时空模式方面的作用。结果显示，许可性和抑制性的神经嵴微环境信号都调节黑色素瘤侵袭的时间和方向，使其与神经嵴迁移模式一致。这些信号包括通过受体酪氨酸激酶的ephrin家族介导的双向信号传导。我们证明，EphB6的重新表达迫使转移性黑色素瘤细胞偏离在鸡胚移植模型中观察到的典型迁移模式。此外，在绒毛尿囊膜（CAM）转移试验中，表达EphB6的黑色素瘤细胞显示出显著降低的转移潜能。这些关于黑色素瘤在胚胎神经嵴和CAM微环境中侵袭的数据确定EphB6是黑色素瘤中的一种转移抑制因子，可能在血管内渗阶段起作用。
Metastatic dissemination drives the high mortality associated with melanoma. However, limitations in visualizing in vivo cell dynamics during metastatic invasion have limited our understanding of these cell behaviors. Recent evidence has revealed that melanoma cells exploit portions of their ancestral embryonic neural crest emigration program to facilitate invasion. What remains to be determined is how embryonic microenvironmental signals influence invasive melanoma cell behavior, and whether these signals are relevant to human disease. To address these questions, we interrogated the role of the neural crest microenvironment in dictating the spatio-temporal pattern of melanoma cell invasion in the chick embryo using 2-photon time-lapse microscopy. Results reveal that both permissive and inhibitory neural crest microenvironmental signals regulate the timing and direction of melanoma invasion to coincide with the neural crest migration pattern. These cues include bi-directional signaling mediated through the ephrin family of receptor tyrosine kinases. We demonstrate that EphB6 re-expression forces metastatic melanoma cells to deviate from the canonical migration pattern observed in the chick embryo transplant model. Furthermore, EphB6-expressing melanoma cells display significantly reduced metastatic potential in a chorioallantoic membrane (CAM) metastasis assay. These data on melanoma invasion in the embryonic neural crest and CAM microenvironments identify EphB6 as a metastasis suppressor in melanoma, likely acting at the stage of intravasation.