Desarrollo de nuevas estrategias terapéuticas contra el cáncer de pulmón en modelos preclínicos

Résumé

DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES AGAINST LUNG CANCER IN PRECLINICAL MODELS Leyre Larzábal Primo School of Sciences, University of Navarra (Spain), 2012 INTRODUCTION: Lung cancer is one of the leading causes of mortality worldwide and the most common cause of death from cancer in men and women. The prognosis of more than 80% of patients with lung cancer is poor, partly because advanced stage at diagnosis precludes curative surgery, and partly because medical treatments are ineffective. In 2007, the 5-year survival rates for men and women diagnosed with lung cancer were 16%. Unfortunately, these percentages have not changed substantially over several decades despite significant advances in diagnosis and new therapeutic options. Although the use of targeted therapies for lung cancer has been a breakthrough in cancer research, only a small proportion of patients benefit from them. Therefore, there is a clear need for new therapeutic alternatives for a more efficacious treatment of this tumor type. OBJETIVE: In this study we proposed two new strategies to reduce lung cancer growth and metastasis: a) Targeting CSCs and non-CSCs with specific compounds and b) study the role of TMPRSS4, a new described serin protease, in lung carcinogenesis, with the future goal of blocking its activity. RESULTS: Salinomycin, a recently identified compound as a selective inhibitor of CSCs, reduced the proportion of ALDH+ CSCs in LLC cell line and reduced the tumorsphere formation capacity, whereas paclitaxel, a commonly used chemotherapeutic drug against NSCLC, increased such population. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules, whereas salinomycin had no effect on primary tumors but reduced lung metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. On the contrary, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis. TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer models including lung cancer. We have shown that knock down of this protease in H358 and H441 cells resulted in a significant reduction in proliferation and invasion in both cell lines. A significant decrease in lung colonization and tumor growth was found when mice were injected with TMPRSS4-depleated H358-derived clones, as compared to controls. Expression of TMPRSS4 showed a >30-fold increase in tumors in comparison to non-malignant samples. Levels in cancer with squamous histology (SCC) were found to be significantly higher than those with adenocarcinoma (AC) histology and high levels of TMPRSS4 were significantly associated with reduced overall survival in patients with SCC histology. A microarray analysis identified miR-205 as an overexpressed gene upon TMPRSS4 downregulation. Levels of miR-205 was found reduced in NSCLC cells compared to non-malignant cells. miR-205 overexpression promoted an epithelial phenotype with increased in E-cadherin and reduced fibronectin. Furthermore, miR-205 inhibited tumor cell migration and metastasis formation in vivo. A further transcriptional and luciferase assays identified integrin α5 (a proinvasive protein) as a new miR-205 target in NSCLC. We have demonstrated for the first time a new molecular connection between TMPRSS4 and integrin α5 through miR-205. CONCLUSION: This study provides new information about the biology of lung cancer and suggests new targets that can be studied in the future as new tools for the treatment of lung cancer.