Yin JuanJuan, Pollock Claire, Tracy Kirsten, Chock Monika, Martin Philip, Oberst Michael, Kelly Kathleen
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, 37 Convent Dr., Rm. 1068, Bethesda, MD 20892, USA.
Mol Cell Biol. 2007 Nov;27(21):7538-50. doi: 10.1128/MCB.00955-07. Epub 2007 Aug 20.
A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis.
转移的一个标志是器官特异性；然而，对于负责肿瘤细胞在靶器官中定植和生长的潜在信号通路却知之甚少。由于酪氨酸激酶受体激活经常与前列腺癌进展相关，我们研究了一种常见的信号中间体——活化的Ras在前列腺癌转移中的作用。检测了Ras下游的三条效应通路，即Raf/细胞外信号调节激酶（ERK）、磷脂酰肌醇3激酶和Ral鸟嘌呤核苷酸交换因子（RalGEF）促进致瘤性、非转移性人前列腺癌细胞系DU145转移的能力。致癌性Ras促进DU145转移至包括骨和脑在内的多个器官。Raf/ERK通路的激活刺激了脑转移定植，而RalGEF通路的激活导致骨转移，这是前列腺癌转移最常见的器官部位。此外，转移性PC3细胞系中RalA的缺失抑制了骨转移，但不影响皮下肿瘤生长。Ral的缺失似乎抑制了前列腺癌细胞在骨中的扩张性生长，而归巢和初始定植受影响较小。这些数据扩展了我们对Ral通路功能作用的理解，并开始确定与器官特异性转移相关的信号通路。
