Kulesa Paul M, Kasemeier-Kulesa Jennifer C, Teddy Jessica M, Margaryan Naira V, Seftor Elisabeth A, Seftor Richard E B, Hendrix Mary J C
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3752-7. doi: 10.1073/pnas.0506977103. Epub 2006 Feb 27.
Human metastatic melanoma cells express a dedifferentiated, plastic phenotype, which may serve as a selective advantage, because melanoma cells invade various microenvironments. Over the last three decades, there has been an increased focus on the role of the tumor microenvironment in cancer progression, with the goal of reversing the metastatic phenotype. Here, using an embryonic chick model, we explore the possibility of reverting the metastatic melanoma phenotype to its cell type of origin, the neural-crest-derived melanocyte. GFP-labeled adult human metastatic melanoma cells were transplanted in ovo adjacent to host chick premigratory neural crest cells and analyzed 48 and 96 h after egg reincubation. Interestingly, the transplanted melanoma cells do not form tumors. Instead, we find that transplanted melanoma cells invade surrounding chick tissues in a programmed manner, distributing along host neural-crest-cell migratory pathways. The invading melanoma cells display neural-crest-cell-like morphologies and populate host peripheral structures, including the branchial arches, dorsal root and sympathetic ganglia. Analysis of a melanocyte-specific phenotype marker (MART-1) and a neuronal marker (Tuj1) revealed a subpopulation of melanoma cells that invade the chick periphery and express MART-1 and Tuj1. Our results demonstrate the ability of adult human metastatic melanoma cells to respond to chick embryonic environmental cues, a subset of which may undergo a reprogramming of their metastatic phenotype. This model has the potential to provide insights into the regulation of tumor cell plasticity by an embryonic milieu, which may hold significant therapeutic promise.
人类转移性黑色素瘤细胞表现出一种去分化的、可塑性的表型，这可能是一种选择性优势，因为黑色素瘤细胞会侵入各种微环境。在过去三十年中，人们越来越关注肿瘤微环境在癌症进展中的作用，目标是逆转转移表型。在此，我们利用胚胎鸡模型，探索将转移性黑色素瘤表型逆转至其起源细胞类型——神经嵴衍生的黑素细胞的可能性。将绿色荧光蛋白标记的成人转移性黑色素瘤细胞移植到宿主鸡迁移前神经嵴细胞附近的鸡胚中，并在鸡蛋重新孵化后48小时和96小时进行分析。有趣的是，移植的黑色素瘤细胞并未形成肿瘤。相反，我们发现移植的黑色素瘤细胞以一种程序性方式侵入周围的鸡组织，沿着宿主神经嵴细胞的迁移途径分布。侵入的黑色素瘤细胞呈现出神经嵴细胞样形态，并在宿主外周结构中聚集，包括鳃弓、背根和交感神经节。对黑素细胞特异性表型标记物（MART-1）和神经元标记物（Tuj1）的分析显示，有一部分侵入鸡外周的黑色素瘤细胞同时表达MART-1和Tuj1。我们的结果表明，成人转移性黑色素瘤细胞能够对鸡胚胎环境信号做出反应，其中一部分细胞可能会经历转移表型的重编程。该模型有可能为胚胎微环境对肿瘤细胞可塑性的调控提供见解，这可能具有重大的治疗前景。
