Effect of the tumor microenvironment on translational control during breast cancer.

摘要

The interplay between epithelial cells, stromal cells and their microenvironment creates a complex but highly regulated tissue structure. The tumor microenvironment is a crucial player in the ability of tumor cells to acquire the ability to survive under hypoxic environments and promote invasiveness.;Translational regulation is essential for the progression of cancer cells and the establishment of carcinomas, as tumor cells need to rapidly proliferate and survive in extreme tumor-host conditions. Molecular cues from the tumor stoma alter the translational machinery, and its activity can be either compromised or fostered depending on cell type or stress, such as hypoxia, which can inhibit cell proliferation. In this dissertation we demonstrate that certain non-cellular components of the tumor microenvironment provide tumor cells with mechanisms to override hypoxia-inhibition of cap-dependent translation and promote invasiveness and migration towards adjacent tissue and distant sites. We show breast tumor microenvironments rich in vitronectin can block hypoxia inhibition of cap-dependent protein synthesis.;Studies described in this dissertation characterize the effect of hypoxia and the adhesion to vitronectin on the activation of different translational regulatory mechanisms to survive under stress and progress by means of increasing angiogenesis and enhancing the invasive potential of tumor cells. We described a mechanism for hypoxia-mediated switching from cap-dependent to IRES-dependent translation in which tumor cells with upregulated 4E-BP1 and high levels of eIF4G, are capable of increasing the translation of pro-angiogenic and tumorigenic IRES-containing mRNAs, thereby promoting angiogenesis and tumor growth in in vivo models. Thus, an IRES-mediated translational program allows tumor cells to increase angiogenesis and increase tumor growth despite hypoxia.;We show that vitronectin engagement of integrin alphavbeta3 under hypoxia results in the inactivation of 4E-BP1 and thus, upregulation of cap-dependent translation despite hypoxia. The translational program established under these conditions promotes the specific upregulation of mRNAs involved in migration and invasion allowing cancer cells to progress in a disadvantageous environment and gain new capabilities to progress and invade other tissues. These results reveal a different mechanism to overcome hypoxia inhibition of protein synthesis with specific upregulation of cap-dependent translation by means of mTORC1 activation downstream integrin signaling.