Goodison Steve, Yuan Jing, Sloan Derek, Kim Ryung, Li Cheng, Popescu Nicholas C, Urquidi Virginia
Department of Pathology, University of Florida Health Science Center, Shands Hospital, Jacksonville, Florida 32209-6511, USA.
Cancer Res. 2005 Jul 15;65(14):6042-53. doi: 10.1158/0008-5472.CAN-04-3043.
The identification of molecular signatures characteristic of tumor cells that are capable of metastatic spread is required for the development of therapeutic interventions to abrogate this lethal process. To facilitate this, we have previously characterized an experimental system in which the role of candidate metastasis-related genes can be screened and tested. Monoclonal cell lines M4A4 and NM2C5 are spontaneously occurring sublines of the MDA-MB-435 cell breast tumor cell line that exhibit phenotypic differences in growth, invasion, and metastatic efficiency in athymic mice. In this study, transcriptional profiles of these cell lines were created using oligonucleotide microarrays representing over 12,000 genes. Intensity modeling and hierarchical clustering analysis identified a 171-gene expression signature that correlated with metastatic phenotype and highlighted several GTPase signaling components. Restoration of one of these GTPases, deleted in liver cancer-1 (DLC-1), in metastatic M4A4 cells to levels observed in the nonmetastatic NM2C5 cell line resulted in the inhibition of migration and invasion in vitro and a significant reduction in the ability of these cells to form pulmonary metastases in athymic mice. These studies show the utility of expression profiling, in an appropriate experimental system, to identify genetic determinants of metastatic sufficiency. The finding that DLC-1 can act as a metastasis-suppressor gene supports an influential role for GTPase signaling in tumor progression.
要开发消除这种致命过程的治疗干预措施，就需要识别能够发生转移扩散的肿瘤细胞的分子特征。为便于开展此项工作，我们之前已对一个实验系统进行了表征，在该系统中可以筛选和测试候选转移相关基因的作用。单克隆细胞系M4A4和NM2C5是MDA - MB - 435乳腺肿瘤细胞系自发产生的亚系，在无胸腺小鼠中，它们在生长、侵袭和转移效率方面表现出表型差异。在本研究中，使用代表超过12,000个基因的寡核苷酸微阵列创建了这些细胞系的转录谱。强度建模和层次聚类分析确定了一个与转移表型相关的171个基因的表达特征，并突出了几个GTP酶信号传导成分。将在转移性M4A4细胞中缺失的一种GTP酶——肝癌缺失-1（DLC-1）恢复到在非转移性NM2C5细胞系中观察到的水平，导致体外迁移和侵袭受到抑制，并且这些细胞在无胸腺小鼠中形成肺转移的能力显著降低。这些研究表明，在合适的实验系统中进行表达谱分析有助于识别转移充分性的遗传决定因素。DLC-1可作为转移抑制基因这一发现支持了GTP酶信号传导在肿瘤进展中的重要作用。
