The impact of macrophages on endothelial cells is potentiated by cycling hypoxia: Enhanced tumor inflammation and metastasis

Abstract

Cycling hypoxia (cyH), neo-angiogenesis, and tumor-associated macrophages are key features of the tumor microenvironment. In this study, we demonstrate that cyH potentiates the induction by unpolarized and M1-like macrophages of endothelial inflammatory phenotype and adhesiveness for monocytes and cancer cells. This process triggers a positive feedback loop sustaining tumor inflammation. This work opens the door for innovative therapeutic strategies to treat tumor inflammation and metastasis.In cancers, the interaction between macrophages and endothelial cells (ECs) regulates tumor inflammation and metastasis. These cells are both affected by cycling hypoxia (cyH), also called intermittent hypoxia, a feature of the tumor microenvironment. cyH is also known to favor tumor inflammation and metastasis. Nonetheless, the potential impact of cyH on the dialog between macrophages and ECs is still unknown. In this work, the effects of unpolarized, M1-like, and M2-like macrophages exposed to normoxia, chronic hypoxia (chH), and cyH on endothelial adhesion molecule expression, pro-inflammatory gene expression, and EC adhesiveness for monocytes and cancer cells were investigated. cyH increased the ability of unpolarized and M1-like macrophages to induce EC inflammation and to increase the expression of the EC endothelial adhesion molecule ICAM1, respectively. Unpolarized, M1-like, and M2-like macrophages were all able to promote EC adhesive properties toward cancer cells. Furthermore, the ability of macrophages (mostly M1-like) to shift EC phenotype toward one allowing cancer cell and monocyte adhesion onto ECs was potentiated by cyH. These effects were specific to cyH because they were not observed with chH. Together, these results show that cyH amplifies the effects of macrophages on ECs, which may promote tumor inflammation and metastasis.

Bioinformatics Analysis and Experimental Verification Define Different Angiogenesis Subtypes in Endometrial Carcinoma and Identify a Prognostic Signature

“…In the past, UCEC was divided into type I and type II (Bokhman classification) . Type I was hormone-dependent, and the pathological type was predominantly endometrioid carcinoma, which had a better prognosis.…”

“…In the past, UCEC was divided into type I and type II (Bokhman classification). 63 Type I was hormone-dependent, and the pathological type was predominantly endometrioid carcinoma, which had a better prognosis. Type II was nonhormone-dependent and had a dismal prognosis, consisting primarily of serous carcinoma, clear cell carcinoma, and carcinosarcoma.…”

The Application of Drugs and Nano-Therapies Targeting Immune Cells in Hypoxic Inflammation

“…Scholars have demonstrated that cycling hypoxia can affect the polarization of tumor-associated macrophages (TAMs) and activate endothelial cell activation through nuclear factor-kappa B (NF-kB) pathway, thus promoting tumor inflammation. 2 Furthermore, hypoxia can promote anaerobic glycolysis, resulting in increased production and release of lactic acid. Prior studies have indicated that lactate escalates the differentiation of T helper 1 cells and the generation of interferon-γ (IFN γ).…”