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Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth.

ABSTRACT: Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1beta promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1beta-induced angiogenesis and cell inflammation. IL-1beta induced neovascularization in the mouse cornea at rates comparable to those of VEGF. Neutrophil infiltration occurred on day 2. Macrophage infiltration occurred on days 4 and 6. The anti-Gr-1 Ab-induced depletion of infiltrating neutrophils did not affect IL-1beta- or VEGF-induced angiogenesis. The former was reduced in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice compared with wild-type mice. After day 4, clodronate liposomes, which kill macrophages, reduced IL-1beta-induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1beta-induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1beta (LLC/IL-1beta) developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1(-/-) mice. A COX-2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration in LLC/IL-1beta. Thus, macrophage involvement might be a prerequisite for IL-1beta-induced neovascularization and tumor progression.

SUBMITTER: Nakao S

PROVIDER: S-EPMC1257532 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Low infiltration of tumor-associated macrophages in high c-Myb-expressing breast tumors.

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Monocyte-Derived Macrophages Are Necessary for Beta-Adrenergic Receptor-Driven Choroidal Neovascularization Inhibition.

Project description:Purpose:Beta-adrenergic receptor (AR) antagonists, like propranolol, inhibit angiogenesis in multiple ocular conditions through an unknown mechanism. We previously showed that propranolol reduces choroidal neovascularization (CNV) by decreasing interleukin-6 levels. Since macrophages are one of the central producers of interleukin-6, we examined whether macrophages are required for propranolol-driven inhibition of choroidal angiogenesis. Methods:We tested the anti-angiogenic properties of propranolol in the choroidal sprouting assay and the laser-induced CNV model. Bone marrow-derived monocytes (BMDMs) were added to the choroidal sprouting assay and Ccr2-/- mice were subjected to laser-induced CNV. Multi-parameter flow cytometry was performed to characterize the ocular mononuclear phagocyte populations after laser injury and during propranolol treatment. Results:Propranolol reduced choroidal angiogenesis by 41% (P < 0.001) in the choroidal sprouting assay. Similarly, propranolol decreased laser-induced CNV by 50% (P < 0.05) in female mice, with no change in males. BMDMs increased choroidal sprouting by 146% (P < 0.0001), and this effect was ablated by propranolol. Beta-AR inhibition had no effect upon laser-induced CNV area in female Ccr2-/- mice. MHCII+ and MHCII- macrophages increased 20-fold following laser treatment in wildtype mice as compared to untreated mice, and this effect was completely attenuated in lasered Ccr2-/- mice. Moreover, propranolol increased the numbers of MHCII+ and MHCII- macrophages by 1.9 (P = 0.07) and 3.1 (P < 0.05) fold in lasered female mice with no change in macrophage numbers in males. Conclusions:Our data suggest that propranolol inhibits angiogenesis through recruitment of monocyte-derived macrophages in female mice only. These data show the anti-angiogenic nature of beta-AR blocker-recruited monocyte-derived macrophages in CNV.

| S-EPMC6894922 | biostudies-literature

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Project description:RalBP1/RLIP76 is a widely expressed multifunctional protein that binds the Ral and R-Ras small GTPases. In the mouse, RLIP76 is nonessential but its depletion or blockade promotes tumorigenesis and heightens the sensitivity of normal and tumor cells to radiation and cytotoxic drugs. However, its pathobiologic functions, which support tumorigenesis, are not well understood. Here, we show that RLIP76 is required for angiogenesis and for efficient neovascularization of primary solid tumors. Tumor growth from implanted melanoma or carcinoma cells was blunted in RLIP76(-/-) mice. An X-ray microcomputed tomography-based method to model tumor vascular structures revealed defects in both the extent and form of tumor angiogenesis in RLIP76(-/-) mice. Specifically, tumor vascular volumes were diminished and vessels were fewer in number, shorter, and narrower in RLIP76(-/-) mice than in wild-type mice. Moreover, we found that angiogenesis was blunted in mutant mice in the absence of tumor cells, with endothelial cells isolated from these animals exhibiting defects in migration, proliferation, and cord formation in vitro. Taken together, our results establish that RLIP76 is required for efficient endothelial cell function and angiogenesis in solid tumors.

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