Identificación, caracterización funcional y clínica de genes prometastásicos en el adenocarcinoma de pulmón

Resumen

Identification, Functional and Clinical Characterization of Prometastatic Genes in Lung Adenocarcinoma Diego Luis-Ravelo, School of Sciences, University of Navarra (Spain), 2010 Lung cancer frequently disseminates to a variety of organs including the skeleton, a process associated with poor prognosis. The aim of this study was to identify key target genes involved in bone metastasis. Using a xenograft model of intracardiac injection (i.c.), we established several bone metastasis models of different histological lung cancer subtypes. Latency time of metastases correlated with different patterns of osteoclastogenic and metalloproteolytic activities. In a model of lung adenocarcinoma we isolated highly metastatic subpopulations (HMS) derived from the parental cell line A549. Using a combination of transcriptomic profiling and robust bioinformatic analysis we identified a subset of significantly overexpressed genes in HMS. Metastatic activity for each single knock-down in a model of i.c. inoculation was unaltered. However, only decreased levels of RhoB showed a significant decreased in metastatic activity. Indeed two different shRhoB cells induced a dramatic decrease in their prometastatic activity as compared to control cells. Moreover, RhoB overexpressing cells showed an increased metastatic activity in the same model. More importantly, in a lung orthotopic model RhoB overexpressing cells were able to disseminate from the lungs in some mice as compared to control cells. These findings were associated with changes in invasiveness and metalloproteolytic activities, whereas osteoclastogenic activities were unaltered. Clinical and in silico analysis in different and independent series of human lung adenocarcinomas revealed a marked association between high RhoB levels and poor survival in patients who received adjuvant chemo- and radiotherapy. Consistently, RhoB levels correlated with taxane resistance and -radioresistance in vitro and in vivo. These data indicate that RhoB acts in early and late steps of the metastatic cascade. In addition, RhoB confers radio- and chemoresistance. Thus, we suggest that RhoB may belong to a novel class of ¿genes of recurrence¿ conferring treatment resistance and endowing cells with metastatic progression functions. This gene may represent a prognosis marker in lung cancer treated patients and a potential therapeutic target.