Two types of hypoxia impact solid tumors, namely chronic hypoxia and cycling hypoxia. Chronic hypoxia and cycling hypoxia have different causes and induce different effects in tumors. Chronic hypoxia is characterized by a very low oxygenation of the cells in the tumor while cycling hypoxia is composed of cycles of low oxygenation (hypoxia) and reoxygenation of the cells in the tumor. Cycling hypoxia promotes, among other things, tumor inflammation and metastasis, both of which are associated with a poor prognosis. Tumors are composed of cancer cells, but also of non-malignant cells. Among the latter, tumor-associated macrophages account for up to half of the tumor-infiltrating immune cells. Macrophages are highly dependent on microenvironmental cues. Depending on these conditions, they can be polarized along an M1-M2 polarization axis, in which M1 macrophages are pro-inflammatory and M2 macrophages are anti-inflammatory. As a result, these cells strongly regulate tumor inflammation. They also strongly promote the dissemination of cancer cells (called metastasis), notably through their impact on tumor blood vessels, and on their main cellular component, the endothelial cells. Endothelial cells strongly regulate metastasis since they constitute a physical barrier that cancer cells must cross twice in order to invade a second organ. Indeed, cancer cells must enter the blood vessels (by intravasation) and then leave them (by extravasation) in order to disseminate. In addition, endothelial cells strongly regulate the infiltration of immune cells into tumors. Reciprocally, monocyte infiltration in secondary tumors strongly increases metastasis. The infiltration of immune cells and cancer cells requires, among other things, their adhesion to endothelial cells, followed by their extravasation. The reasons for the induction of inflammation by cycling hypoxia are still unknown, as is the effect of cycling hypoxia on macrophages. In this thesis, the effects of cycling hypoxia on murine and human macrophages were investigated. Specifically, M0 (unpolarized), M1 or M2 macrophages were exposed to cycling hypoxia, chronic hypoxia or normoxia. The impact of these treatments on the pro-inflammatory phenotype of macrophages was studied. Cycling hypoxia induced a pro-inflammatory phenotype in M0 macrophages and increased the pro-inflammatory phenotype of M1 macrophages. The effect of cycling hypoxia was specific as it was not observed with chronic hypoxia. Furthermore, the JNK/p65 signalling pathway was shown to be involved in the induction of this phenotype in human macrophages upon exposure to cycling hypoxia. Since macrophages have a strong impact on endothelial cells, the effect of macrophages exposed to cycling hypoxia on the phenotype of endothelial cells was studied. In particular, the effect of these macrophages on the pro-inflammatory phenotype of endothelial cells and on their ability to allow adhesion of monocytes and cancer cells was studied. We showed that macrophages exposed to cycling hypoxia increased the pro-inflammatory phenotype of endothelial cells, increased their expression of adhesion molecules and increased the ability of endothelial cells to allow monocytes and cancer cells to adhere to them. Interestingly, these effects were most strongly induced by macrophages exposed to cycling hypoxia. To summarize, during this thesis, we showed that cycling hypoxia induces a pro-inflammatory phenotype in M0 and M1 macrophages via JNK/p65 signaling pathway. Furthermore, cycling hypoxia potentiates the impact of macrophages on the induction of a pro-metastatic phenotype in endothelial cells. These findings could explain some of the mechanisms by which cycling hypoxia induces tumor inflammation and metastasis.
Study of the effects of cycling hypoxia on macrophages and on the interaction between macrophages and endothelial cells: role in the promotion of tumor inflammation
DELPRAT, V. (Author). 24 Aug 2021
Student thesis: Doc types › Doctor of Sciences