Hypoxia-Inducible Factor-2α Regulates GM-CSF–Derived Soluble Vascular Endothelial Growth Factor Receptor 1 Production from Macrophages and Inhibits Tumor Growth and Angiogenesis

Abstract

Macrophage secretion of VEGF in response to the hypoxic tumor microenvironment contributes to tumor growth, angiogenesis, and metastasis. We have recently demonstrated that macrophages stimulated with GM-CSF at low O2 secrete high levels of a soluble form of the VEGF receptor (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using siRNA targeting to deplete HIF-1α or HIF-2α in murine macrophages, we found that macrophage production of sVEGFR-1 in response to low O2 was dependent on HIF-2α, while HIF-1α specifically regulated VEGF production. In our current report, we evaluated the growth of B16F10 malignant melanoma in mice with a monocyte/macrophage-selective deletion of HIF-1α or HIF-2α (HIF-1αflox/flox-or HIF-2αflox/+/LysMcre mice). GM-CSF treatment increased intra-tumoral VEGF and sVEGFR-1 in control mice, an effect that was associated with a decrease in microvessel density. GM-CSF treatment of HIF-1αflox/flox/LysMcre mice induced sVEGFR-1 but not VEGF, resulting in an overall greater reduction in tumor growth and angiogenesis compared to control mice. In addition, real-time PCR for melanoma-specific genes revealed a significantly reduced presence of lung micrometastases in HIF-1αflox/flox/LysMcre mice treated with GM-CSF. Conversely, GM-CSF treatment induced VEGF but not sVEGFR-1 in HIF-2αflox/+/LysMcre mice, and correspondingly, GM-CSF did not decrease tumor growth, angiogenesis, or lung metastasis in these mice. This study reveals opposing roles for the HIFs in the regulation of angiogenesis by tumor-associated macrophages, and suggests that administration of GM-CSF might be an effective means of inducing sVEGFR-1 and inhibiting tumor growth and angiogenesis in patients with melanoma.

Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth

“…8A-C), indicating that blood vessels in EL4-IL-33 tumors were not fully functional. Consistent with the lower degree of angiogenesis in EL4-IL-33 tumors, these tumors expressed lower levels of angiogenesis-promoting genes (HIF-1a, VEGF, plateletderived growth factor-B, and TGF-b) but higher levels of angiogenesis-inhibiting genes (HIF-2a and soluble VEGF receptor) (29,30) (Fig. 8E).…”

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

“…The increase in VEGF membrane-bound and soluble type-2 receptor mRNA may be explained by the observation that VEGF increase VEGFR1 and VEGFR2 mRNA expression (Wang et al, 2000), and hypoxia stimulates the expression of membrane-bound (Kremer et al, 1997) and soluble-receptor isoforms (Roda et al, 2011). However, while the mRNA expression for VEGFR1 is maintained, expression of VEGFR2 declines on day 18 of the cycle.…”

Metabolic reprogramming and two-compartment tumor metabolism

“…However, no effects on tumor growth and metastasis formation were observed in HIF2α (-/-) null background, relative to control animals. 26 distinct function(s) in the pathogenesis of breast cancer, and their effects are compartmentspecific (Fig. 8).…”