Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer

Abstract

Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription factors HIF-1a and HIF-2a, regulates TEM function in the hypoxic tumor microenvironment. We orthotopically implanted PyMT breast tumor cells into the mammary fat pads of syngeneic LysMcre, HIF-1a fl/fl /LysMcre, or HIF-2a fl/fl /LysMcre mice and evaluated the tumor TEM population. There was no difference in the percentage of tumor macrophages among the mouse groups. In contrast, HIF-1a fl/fl /LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2a fl/fl /LysMcre mice. Proangiogenic TEMs in macrophage HIF-2a-deficient tumors presented significantly more CD31 + microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of proangiogenic TEMs in macrophage HIF-1a-deficient tumors presented significantly less microvessel density but tumor vessels that were more functional as lectin injection revealed more perfusion, and functional electron paramagnetic resonance analysis revealed more oxygen in those tumors. Macrophage HIF-1a-deficient tumors also responded significantly to chemotherapy. These data introduce a previously undescribed and counterintuitive prohypoxia role for proangiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2a.

Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer

“…As previously discussed in this review ( Figure 2 ), TEMs play a role in angiogenesis; however, in the setting of cancer, where the number of TEMs is elevated, TEMs are responsible for aberrant and dysfunctional angiogenesis [ 53 ]. In the transgenic rat insulin promoter (RIP)-T antigen (Tag) murine model of metastatic pancreatic neuroendocrine tumor (PNET), which causes carcinogenesis of β-cells of the pancreas and is commonly used to study tumor angiogenesis [ 135 ], inhibition of TIE2 on TEMs reduces TIE2 + myeloid infiltration resulting in reduced microvessel density, less vascular permeability, and blockade of tumor cell intravasation mediated by TIE2 Hi /VEGF-A Hi macrophages [ 136 ].…”

“…We recently reported that in a PyMT mouse model of breast cancer, breast tumors containing wild type and HIF-2α-deficient macrophages (containing only HIF-1α) had elevated numbers of tumor TEMs, increased hypoxia, and poor vessel perfusion that limited docetaxel delivery and efficacy. Mice with macrophages containing only HIF-2α (HIF-1α-deficient) had a reduced number of TEMs, better vascular architecture, and increased oxygen that enabled better perfusion and enhanced tumor cytotoxicity [ 53 ]. Like TEMs, a subset of neutrophils has been shown to express TIE2 [ 75 , 76 ].…”

“…Since vessel integrity was not investigated here, it is possible that Bv8 inhibition may modulate vessel function in these tumors, which enhanced the effect of chemotherapy. For example, we have shown that HIF-1α knockdown in myeloid cells decreases vessel density in a murine breast tumor model, but these vessels are more functional, with higher tumor oxygen tension, enhanced vessel perfusion, and ultimately a significant response to chemotherapy when compared to the wild-type controls [ 53 ]. It is also possible that macrophages recruit a specific pro-angiogenic subset of neutrophils to the TME through the VEGFR/VEGF-A axis.…”

“…Another important subtype of macrophages includes those expressing endothelial receptor TIE2 (TEMs) [ 51 ] that are specific for the four angiopoietin ligands (ANG1-4) [ 52 ]. TIE2/ TEK was once thought to be solely expressed on cells comprising the endothelium until the discovery of their expression on a myeloid population, TEMs ( Table 1 ) [ 53 ]. Most relevant to this review are ANG1 and ANG2 as their ratio in a hypoxic tumor setting (high ANG2:low ANG1) regulate important differences between physiological angiogenesis and pathological vascular dysfunction sustaining hypoxia that predicts worse prognosis in patients with solid tumors, including breast cancer and pancreatic cancer [ 54 , 55 , 56 , 57 , 58 , 59 ].…”

A hypoxia-related gene pairs signature for predicting overall survival in lung adenocarcinoma

“…Hypoxia, or lack of oxygen, is a characteristic feature of most solid tumor [6]. Increasing evidence has found that the hypoxic environment in tumors directly stimulated the malignant properties of cancers, including advanced aggressiveness and resistance to therapies [7][8][9][10]. Meanwhile, the in ltration of immune cells in the tumor is also a crucial component that can affect the tumor invasion and metastasis [11].…”