del Peso L, Hernández-Alcoceba R, Embade N, Carnero A, Esteve P, Paje C, Lacal J C
Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain.
Oncogene. 1997 Dec 18;15(25):3047-57. doi: 10.1038/sj.onc.1201499.
Rho proteins have been implicated in the regulation of multiple signal transduction processes. Some of the members of this family, including the rho gene from Aplysia californica and the human genes (rhoA, rhoB and rac-1), are proto-oncogenes since when properly mutated they can induce cell transformation, and the generated rho-transformed cells are tumorigenic when inoculated into mice. In addition to their tumorigenic activity, there is evidence suggesting that Rho proteins may contribute to the metastatic phenotype. However, all the experiments implicating Rho proteins or Rho-regulating proteins in the induction of metastatic potential are either indirect or have been performed in vitro. In this study we investigated whether cells transformed by rho oncogenes do have metastatic potential in vivo. We present evidence that cells transformed by the Aplysia californica rho gene, when injected directly into the blood stream are able to efficiently colonize lungs and secondary organs, consistent with the acquisition of the metastatic potential. Moreover, tumors derived from subcutaneous injections of these rho-transformed cells are also able to metastasize in distant organs, a strong support to the hypothesis that Rho proteins play a role in the metastatic phenotype. Finally, cells transformed by the human oncogenes dbl, vav and ost, three well-known guanine exchange factors for members of the Rho family, or cells transformed by the activated human rac-1 or rhoA genes do also have metastatic potential when injected into the blood stream. These results demonstrate that signaling pathways regulated by Rho proteins play an important role in the acquisition of the metastatic phenotype in vivo.
Rho蛋白已被证明参与多种信号转导过程的调控。该家族的一些成员，包括加州海兔的rho基因以及人类基因（rhoA、rhoB和rac - 1），都是原癌基因，因为当它们发生适当突变时可诱导细胞转化，并且产生的rho转化细胞接种到小鼠体内时具有致瘤性。除了其致瘤活性外，有证据表明Rho蛋白可能与转移表型有关。然而，所有涉及Rho蛋白或Rho调节蛋白诱导转移潜能的实验要么是间接的，要么是在体外进行的。在本研究中，我们调查了由rho癌基因转化的细胞在体内是否确实具有转移潜能。我们提供的证据表明，由加州海兔rho基因转化的细胞直接注入血流后能够有效地在肺部和次级器官中定植，这与获得转移潜能一致。此外，由皮下注射这些rho转化细胞产生的肿瘤也能够转移到远处器官，这有力地支持了Rho蛋白在转移表型中起作用的假说。最后，由人类癌基因dbl、vav和ost（Rho家族成员的三种著名鸟嘌呤交换因子）转化的细胞，或由活化的人类rac - 1或rhoA基因转化的细胞注入血流后也具有转移潜能。这些结果表明，由Rho蛋白调节的信号通路在体内转移表型的获得中起重要作用。
