Evaluación preclínica y caracterización molecular de terapias antiangiogénicas en carcinomas neuroendocrinos. Papel de Galectina-1 como mediador de respuesta

Résumé

Neuroendocrine carcinomas (NEC) are considered a rare disease. Approximately, they represent 10- 20% of all diagnosed neuroendocrine neoplasms (NEN), and their median survival is around 10 months. These tumors debut with advanced disease and metastasis at diagnosis. So far, chemotherapy scheme based on cisplatin/etoposide is the unique therapy as first line, and after relapse, the second treatment line is not well defined. NECs show a high angiogenic activity characterized by an over expression of proangiogenic factors, such as vascular growth factor (VEGF) family. For this reason, this work proposes the in vivo evaluation of two antiangiogenic treatments, aflibercept and bevacizumab, in two murine xenograft models developed from human colon and lung CNE cell lines. Our results show that both drugs exert a high antitumor activity in both models, being especially striking the "tumor stability" induced by aflibercept in the lung model. Regarding to the potential mechanisms associated with the antitumoral activity of antiangiogenic therapies analyzed in this study, the results show that the differences of tumor growth inhibition by aflibercept between both xenograft models are due, at least partially, to the different protein levels of Galectin-1 (Gal-1). Tumors derived from lung NEC cell line showed high levels of Gal-1 that were significantly reduced by aflibercept. This reduction directly affects essential processes for tumor development such as cell invasion, transition epithelium-mesenchyma and the extracellular matrix remodeling. These effects were not observed in xenograft model from colon CNE cell line whose tumors show almost undetectable Gal-1 levels, suggesting that this protein could be a potential predictive marker of aflibercept treatment. Analysis of Gal-1 in a set of patients with NEC confirmed that tumors with pancreatic or pulmonary origin showed high levels of this protein whereas colon NECs showed similar levels as their matched normal tissues. These results together with the high efficacy of aflibecept demonstrated in the preclinical model with high levels of Gal-1 open the door to the use of this antiangiogenic as therapy in patients whose tumors overexpress Gal-1.