Hypoxia and HIF- activation in endothelial cells affect metastatic pre-disposition in a time- and isoform-specific manner

The metastatic cascade is initiated at the primary tumor, but the compliance of the tumor-free distant organs in their own metastatic colonization is mostly understudied. Metastases occur primarily through hematogenous dissemination, involving multiple steps where the tumor cells need to exploit or manipulate the endothelial barrier. Unlike that in the primary tumour microenvironment, the vasculature at the distant (pre)metastatic site is presumably intact. A healthy microvascular network restricts extravasation, a limiting step for metastatic seeding; and a secondary angiogenic switch is necessary for secondary tumour proliferation. Both events- extravasation and secondary proliferation - require that the vasculature’s compliance with tumor cells.
We know from our and others’ studies that endothelial cell (EC) behavior and physiology are intrinsically connected to the activation of hypoxia inducible transcription factors (HIF), and that deletion of these isoforms in EC have major effects in metastatic take. HIF activation in EC affects their proliferation, survival, monolayer permeability and intercellular communication, and occurs in response to organ status or systemic signals. Here, we investigated the role of activation EC-specific HIF- isoforms by manipulating their stabilization short and prolonged hypoxia exposure, and showed that (1) EC HIF-1 in the lung is transiently activated during acute hypoxia, where it (2) creates a pro-metastatic microenvironment, resulting in (3) disruption of the endothelial barrier and recruitment of pro-metastatic macrophages. Stabilization of HIF-2 was seen highest after prolonged hypoxia, and had a protective effect on microvascular integrity and metastasis. These results were validated using lung EC-specific deletion of either HIF-1 or HIF-2.