Estudio de la respuesta a hipoxia aguda de células de endotelio linfático. Influencia en la metástasis tumoral

Résumé

STUDY OF LYMPHATIC ENDOTHELIAL CELLS RESPONSE TO HYPOXIA. INFLUENCE ON TUMORAL METASTASIS The lymphatic vasculature comprises a tree-like hierarchy of vessels that transports extravasated fluid and macromolecules in a single direction from tissues back to the blood circulation. It exerts important functions in immune surveillance, tissue fluid homeostasis and fat absorption, being involved in wound healing and some pathological processes, such as lymphedema and cancer metastasis. It is well established that decreases in the tumor oxygen supply promote its vascularization, but currently, little is known about the effect of hypoxia on the lymphatic vasculature. To clarify this, we used cDNA microarrays to study the mRNA expression of hypoxia exposed lymphatic endothelial cells (LEC). We extended the transcriptome analysis with some functional assays showing that under low oxygen conditions, lymphatic endothelial cells produced reactive oxygen species, showed impaired proliferation, experimented major changes in their cytoskeletal architecture and increased their cell attachment to the extracellular matrix. We also demonstrated that the integrin-extracellular matrix adaptor protein TGFBI (transforming growth factor beta induced) mediates lymphatic endothelial cells adhesion and migration through the extracellular matrix. Besides, we showed that TGFBI mediates LEC adhesion and migration through its interaction with the β3 integrin. We also demonstrated that hypoxia promotes the adhesion of NSCLC to the endothelium and that CXCR4 mediates NSCLC adhesion and transmigration through the lymphatic endothelium. In short, we study the response to hypoxia of lymphatic endothelial cells and suggest targets to block tumor metastasis through these vessels.