Neutrophils and Angiogenesis: Potential Initiators of the Angiogenic Cascade

Benelli, Roberto; Albini, Adriana; Noonan, Douglas M.

doi:10.1159/000071560

Cited by 48 publications

(33 citation statements)

References 62 publications

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“…In contrast with our findings, other studies reported that in the corneal micropocket assay, the angiogenic response to CXC-ELR ϩ chemokines occurs in the absence of neutrophil inflammation, thus pointing to a possible direct interaction of these ligands with endothelial cells (2,3). These contrasting results might be due to inherent differences in the two models, particularly in light of the immune privilege of ocular tissues (36). However, in a typical inflammatory model of cornea neovascularization, like that induced in response to Pseudomonas aeruginosa infection, the resulting angiogenic response was shown to be associated with neutrophil infiltration and dependent on CXCL1/MIP-2 and VEGF-A production (37).…”

Section: Discussioncontrasting

confidence: 99%

CXCL1/Macrophage Inflammatory Protein-2-Induced Angiogenesis In Vivo Is Mediated by Neutrophil-Derived Vascular Endothelial Growth Factor-A

Scapini

Morini

Tecchio

et al. 2004

The Journal of Immunology

224

172

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The angiogenic activity of CXC-ELR+ chemokines, including CXCL8/IL-8, CXCL1/macrophage inflammatory protein-2 (MIP-2), and CXCL1/growth-related oncogene-α in the Matrigel sponge angiogenesis assay in vivo, is strictly neutrophil dependent, as neutrophil depletion of the animals completely abrogates the angiogenic response. In this study, we demonstrate that mice deficient in the src family kinases, Hck and Fgr (hck−/−fgr−/−), are unable to develop an angiogenic response to CXCL1/MIP-2, although they respond normally to vascular endothelial growth factor-A (VEGF-A). Histological examination of the CXCL1/MIP-2-containing Matrigel implants isolated from wild-type or hck−/−fgr−/− mice showed the presence of an extensive neutrophil infiltrate, excluding a defective neutrophil recruitment into the Matrigel sponges. Accordingly, neutrophils from hck−/−fgr−/− mice normally migrated and released gelatinase B in response to CXCL1/MIP-2 in vitro, similarly to wild-type neutrophils. However, unlike wild-type neutrophils, those from hck−/−fgr−/− mice were completely unable to release VEGF-A upon stimulation with CXCL1/MIP-2. Furthermore, neutralizing anti-VEGF-A Abs abrogated the angiogenic response to CXCL1/MIP-2 in wild-type mice and CXCL1/MIP-2 induced angiogenesis in the chick embryo chorioallantoic membrane assay, indicating that neutrophil-derived VEGF-A is a major mediator of CXCL1/MIP-2-induced angiogenesis. Finally, in vitro kinase assays confirmed that CXCL1/MIP-2 activates Hck and Fgr in murine neutrophils. Taken together, these data demonstrate that CXCL1/MIP-2 leads to recruitment of neutrophils that, in turn, release biologically active VEGF-A, resulting in angiogenesis in vivo. Our observations delineate a novel mechanism by which CXCL1/MIP-2 induces neutrophil-dependent angiogenesis in vivo.

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Section: Discussioncontrasting

confidence: 99%

CXCL1/Macrophage Inflammatory Protein-2-Induced Angiogenesis In Vivo Is Mediated by Neutrophil-Derived Vascular Endothelial Growth Factor-A

Scapini

Morini

Tecchio

et al. 2004

The Journal of Immunology

224

172

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“…The inflammatory microenvironment of tumours is characterized by the presence of host leucocytes, both in the stroma and in the vicinity of tumours (21). TIGs potentially can promote tumour progression via stimulation of angiogenesis and invasion (9)(10)(11)(12) or stimulate tumour growth by releasing growth factors (13). Accordingly, in this study TIGs were frequently detected in areas of tumour invasion, and were significantly associated with depth of tumour invasion, lymph node metastasis, poor differentiation and TNM stage.…”

Section: Discussionmentioning

confidence: 53%

It is possible that tumour-infiltrating granulocytes promote tumour progression

Liu

Ubukata²,

Takemura³

et al. 2009

Oncol Rep

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Abstract. Several lines of evidence indicate that tumourinfiltrating granulocytes (TIGs) promote tumour growth and progression. However, the prognostic significance of TIGs, the relationship beween TIGs and Fas ligand (FasL) expressed on tumour cells remains unclear and warrants investigation. Using immunnostaining, we retrospectively investigated TIGs and FasL in 130 tissue specimens from gastric carcinoma. We analyzed the correlation among these markers, their association with clinicopathologic features and prognosis. The number of TIGs was significantly associated with FasLexpression (P=0.002). Further, TIGs were significantly associated with depth of tumour invasion, lymph node metastasis and tumour stage. Calculating the prognostic relevance, in multivariate analysis, TIGs [relative risk (RR)=1.014; 95% CI=1.002-1.027; P=0.015] and tumour stage were statistically significant factors for survival. Our results suggest that TIGs are conveniently measured by the immunostaining method, and possibly serve as an independent factor of prognosis in patients with gastric carcinoma. This is based on the fact that TIGs were significantly associated with tumour stage and shorter survival time.

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“…However neutrophils are associated with tissue damage and necrosis in late disease and are a feature of granulomas in gene-deletion models associated with increased susceptibility to tuberculosis (27)(28)(29)(30)(31)(32)(33). Neutrophils release mediators that likely contributed to the angiogenesis in the trehalose mycolate-bearing matrices, evident at 4 days postinjection (34). Several leukocyte products play a role in angiogenesis, including VEGF, IL-1, IL-6, IL-8, basic fibroblast growth factor, reactive nitrogen intermediates, TNF-␣, and TGF-␤ (35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

“…Several leukocyte products play a role in angiogenesis, including VEGF, IL-1, IL-6, IL-8, basic fibroblast growth factor, reactive nitrogen intermediates, TNF-␣, and TGF-␤ (35)(36)(37)(38)(39). An appreciation for the role of neutrophils in angiogenesis is growing; neutrophils are sources of proangiogenic mediators including VEGF, IL-8, hepatocyte growth factor, and platelet-activating factor, and they can recruit additional leukocytes, like macrophages that contribute further to the proangiogenic cascade (34,40). VEGF, an acute-phase proinflammatory response cytokine, increases vascular permeability and monocyte recruitment.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Activity of Released Cell Wall Lipids ofMycobacterium bovisBacillus Calmette-Guérin Is Due Principally to Trehalose Mycolates

Geisel

Sakamoto

Russell

et al. 2005

The Journal of Immunology

174

154

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The hallmark of Mycobacterium-induced pathology is granulomatous inflammation at the site of infection. Mycobacterial lipids are potent immunomodulators that contribute to the granulomatous response and are released in appreciable quantities by intracellular bacilli. Previously we investigated the granulomagenic nature of the peripheral cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin (BCG) by coating the lipids onto 90-μm diameter microspheres that were mixed into Matrigel matrix with syngeneic bone marrow-derived macrophages and injected i.p. into mice. These studies demonstrated that BCG lipids elicit proinflammatory cytokines and recruit leukocytes. In the current study we determined the lipids responsible for this proinflammatory effect. BCG-derived cell wall lipids were fractionated and purified by liquid chromatography and preparative TLC. The isolated fractions including phosphatidylinositol dimannosides, cardiolipin, phosphatidylglycerol, phosphatidylethanolamine, trehalose monomycolate, trehalose dimycolate, and mycoside B. Trehalose dimycolate, when delivered to bone marrow-derived murine macrophages, induced the greatest secretion of IL-1β, IL-6, and TNF-α in vitro. Trehalose dimycolate similarly induced the greatest secretion of these proinflammatory cytokines in ex vivo matrices over the course of 12 days. Trehalose monomycolate and dimycolate also induced profound neutrophil recruitment in vivo. Experiments with TLR2 or TLR4 gene-deficient mice revealed no defects in responses to trehalose mycolates, although MyD88-deficient mice manifested significantly reduced cell recruitment and cytokine production. These results demonstrate that the trehalose mycolates, particularly trehalose dimycolate, are the most bioactive lipids in the BCG extract, inducing a proinflammatory cascade that influences granuloma formation.

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Neutrophils and Angiogenesis: Potential Initiators of the Angiogenic Cascade

Cited by 48 publications

References 62 publications

CXCL1/Macrophage Inflammatory Protein-2-Induced Angiogenesis In Vivo Is Mediated by Neutrophil-Derived Vascular Endothelial Growth Factor-A

CXCL1/Macrophage Inflammatory Protein-2-Induced Angiogenesis In Vivo Is Mediated by Neutrophil-Derived Vascular Endothelial Growth Factor-A

It is possible that tumour-infiltrating granulocytes promote tumour progression

In Vivo Activity of Released Cell Wall Lipids ofMycobacterium bovisBacillus Calmette-Guérin Is Due Principally to Trehalose Mycolates

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