Hypoxia Preconditioning Affects Metastatic Seeding And Proliferation Through Vascular And Immune Function, In A Process Regulated By Lung Endothelial Hifa

Metastases are the main cause of mortality in solid cancers. Current evidence shows that tumor cells are present in circulation from early stages of malignancy, and this initial dissemination implies that early diagnosis alone is not a consistent or reliable predictor of outcome. A deeper understanding of factors affecting extravasation and secondary proliferation is crucial to develop strategies to prevent and/or treat metastatic disease. Our research and that of others have shown that tumor dissemination rely on properties of the tumor cells, but also on the individual cell types in the microenvironments, as well as on the physiological context in the host organ. Tumor progression is, consequently, a function of the individual cell types in the microenvironments of the primary tumor and metastatic sites. Activation of hypoxia-inducible factors (HIFs) in most solid tumor types is directly correlated with poor prognosis. However, we have shown that when in host organ cells, and specifically endothelial cells, the role of HIF is isoform-specific: mice lacking endothelial HIF-1α develop less lung metastases, whereas those lacking endothelial HIF-2α have more. This is a very intriguing phenomenon that revealed a decisive role for the endothelium in allowing or preventing metastatic success, shown to be, in part, dependent on an imbalanced production of nitric oxide (NO), with clear NO-driven effects on vessel function. Upon exposure of mice to low atmospheric oxygen levels, we found that there is a time-dependent activation of HIF-1α and HIF-2α in lung tissue, which results in differential gene expression and inflammatory response/inflammatory cell recruitment, affecting both extravasation and secondary proliferation of circulating tumor cells. In this study, mice were hypoxia-conditioned prior to intravenous injection of cancer cells, to investigate the effect of hypoxia-driven vascular changes on pulmonary metastases. Mice exposed to either short or prolonged hypoxia show increased number of lung monocytes when compared to normoxic controls. However, acute hypoxia (24h), which correlates with higher HIF-1α levels, results in increased numbers of lung tumors, whereas chronic hypoxia exposure (10d, higher HIF-2α activation) results in fewer and less proliferative tumors. Using a variety of approaches, including cytokine and transcriptional screens, imaging and cell-specific HIF-deletion models, both in vivo and ex-vivo, we are investigating which parameters affecting metastatic disease are changed during acute and prolonged hypoxia, resulting in differential metastatic incidence. We found that both endothelial permeability and endothelial-derived signaling is affected differently upon acute or chronic hypoxia stimulus, with also different impact on extravasation and immune cell recruitment and activation. We aim to identify what molecular mechanism(s) underlying hypoxia, HIF and vascular endothelium responses condition the establishment of secondary tumors. Citation Format: Cristina Branco, Helene Rundqvist, Renato Colaco, Randall S. Johnson. Hypoxia preconditioning affects metastatic seeding and proliferation through vascular and immune function, in a process regulated by lung endothelial HIFa. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr PR03.