Vascular Adhesion Protein-1 Enhances Tumor Growth by Supporting Recruitment of Gr-1+CD11b+ Myeloid Cells into Tumors

Marttila-Ichihara, Fumiko; Auvinen, Kaisa; Elima, Kati; Jalkanen, Sirpa; Salmi, Marko

doi:10.1158/0008-5472.can-09-1205

Cited by 60 publications

(58 citation statements)

References 44 publications

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“…This finding supports previous reports revealing the key role of VAP-1 in angiogenesis-related diseases, including cancer 13 and age-related macular degeneration. 5 To date, molecular diagnosis has not been introduced to patient care and need is great for in vivo molecular markers of angiogenic disease.…”

Section: Discussionsupporting

confidence: 93%

“…A recent article also showed impaired leukocyte infiltration in cancer in VAP-1-deficient mice. 13 Tumor lymphangiogenesis in VAP-1Ϫ/Ϫ mice does not differ from wild type. 13 During tumor development and metastasis, cytokines such as VEGF-A and IL-1␤ are up-regulated.…”

Section: Vap-1 In Lymph-and Angiogenesis 1919mentioning

confidence: 98%

“…13 Tumor lymphangiogenesis in VAP-1Ϫ/Ϫ mice does not differ from wild type. 13 During tumor development and metastasis, cytokines such as VEGF-A and IL-1␤ are up-regulated. 8 Our data show that VAP-1 blockade inhibits IL-1␤-induced but not VEGF-A-induced lymphangiogenesis, indicating cytokine dependency of leukocyte-mediated lymphangiogenesis.…”

Section: Vap-1 In Lymph-and Angiogenesis 1919mentioning

confidence: 98%

“…8,11,12 VAP-1 inhibition reduces pathological angiogenesis by diminishing macrophage infiltration 5 but is not involved in physiologic vessel formation. 13 VAP-1 contributes to tumor angiogenesis but not lymphangiogenesis through its impact on leukocytes recruitment. 13 Recent work shows that polarization of mononuclear phagocytes into classically activated (M1) and alternatively activated (M2) macrophages is a decisive factor in various diseases and that M2 macrophages promote angiogenesis.…”

mentioning

confidence: 96%

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VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

Nakao

Noda

Zandi

et al. 2011

The American Journal of Pathology

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Vascular adhesion protein-1 (VAP-1) contributes to inflammatory and angiogenic diseases, including cancer and age-related macular degeneration. It is expressed in blood vessels and contributes to inflammatory leukocyte recruitment. The cytokines IL-1␤ and vascular endothelial growth factor A (VEGF-A) modulate angiogenesis, lymphangiogenesis, and leukocyte infiltration. The lymphatic endothelium expresses intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which facilitate leukocyte transmigration into the lymphatic vessels. However, whether lymphatics express VAP-1 and whether they contribute to cytokine-dependent lymph-and angiogenesis are unknown. We investigated the role of VAP-1 in IL-1␤-and VEGF-A-induced lymph-and angiogenesis using the established corneal micropocket assay. IL-1␤ increased VAP-1 expression in the inflamed cornea. Our in vivo molecular imaging revealed significantly higher VAP-1 expression in neovasculature than in the preexisting vessels. VAP-1 was expressed in blood but not lymphatic vessels in vivo. IL-1␤-induced M2 macrophage infiltration and lymphand angiogenesis were blocked by VAP-1 inhibition. In contrast, VEGF-A-induced lymph-and angiogenesis were unaffected by VAP-1 inhibition. Our results indicate a key role for VAP-1 in lymph-and angiogenesisrelated macrophage recruitment. VAP-1 might become a new target for treatment of inflammatory lymph-and angiogenic diseases, including cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Vap-1 In Lymph-and Angiogenesis 1919mentioning

confidence: 98%

Section: Vap-1 In Lymph-and Angiogenesis 1919mentioning

confidence: 98%

mentioning

confidence: 96%

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VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

Nakao

Noda

Zandi

et al. 2011

The American Journal of Pathology

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“…We have found that tumor progression is retarded in VAP-1-deficient mice (22). In this study, we therefore evaluated the effects of anti-VAP-1 Abs and SSAO inhibitors on leukocyte recruitment into tumors and tumor progression.…”

mentioning

confidence: 99%

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

Marttila-Ichihara

Castermans

Auvinen

et al. 2010

The Journal of Immunology

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Vascular adhesion protein-1 (VAP-1) is an endothelial, cell surface–expressed oxidase involved in leukocyte traffic. The adhesive function of VAP-1 can be blocked by anti–VAP-1 Abs and small-molecule inhibitors. However, the effects of VAP-1 blockade on antitumor immunity and tumor progression are unknown. In this paper, we used anti–VAP-1 mAbs and small-molecule inhibitors of VAP-1 in B16 melanoma and EL-4 lymphoma tumor models in C57BL/6 mice. Leukocyte accumulation into tumors and neoangiogenesis were evaluated by immunohistochemistry, flow cytometry, and intravital videomicroscopy. We found that both anti–VAP-1 Abs and VAP-1 inhibitors reduced the number of leukocytes in the tumors, but they targeted partially different leukocyte subpopulations. Anti–VAP-1 Abs selectively inhibited infiltration of CD8-positive lymphocytes into tumors and had no effect on accumulation of myeloid cells into tumors. In contrast, the VAP-1 inhibitors significantly reduced only the number of proangiogenic Gr-1+CD11b+ myeloid cells in melanomas and lymphomas. Blocking of VAP-1 by either means left tumor homing of regulatory T cells and type 2 immune-suppressing monocytes/macrophages intact. Notably, VAP-1 inhibitors, but not anti–VAP-1 Abs, retarded the growth of melanomas and lymphomas and reduced tumor neoangiogenesis. The VAP-1 inhibitors also reduced the binding of Gr-1+ myeloid cells to the tumor vasculature. We conclude that tumors use the catalytic activity of VAP-1 to recruit myeloid cells into tumors and to support tumor progression. Small-molecule VAP-1 inhibitors therefore might be a potential new tool for immunotherapy of tumors.

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Quinone Cofactors

Lang

Klinman

2013

Encyclopedia of Life Sciences

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Quinone cofactors are used by several classes of enzymes, which catalyse the oxidation of biogenic amines and alcohols, to help catalyse these reactions. Before 1990 only one cofactor, the peptide‐derived pyrroloquinoline quinone had been identified. During 1990–2001, however, four new quinone prosthetic groups derived from naturally occurring amino acids were discovered. The first protein‐derived, nondissociable cofactor identified was 2,4,5‐trihydroxyphenylalanine quinone, designated topaquinone (TPQ) in copper amine oxidases . The discovery of TPQ led to the identification of a series of new quinone cofactors, including lysine tyrosylquinone (LTQ) in lysyl oxidase, cysteine tryptophylquinone (CTQ) in quinohaemoprotein amine dehydrogenase and tryptophan tryptophylquinone (TTQ) in bacterial methylamine dehydrogenase . These cofactors contribute electrophillic capabilities (and stabilise free radical intermediates) that naturally occurring, unmodified amino acid side chains are unable to provide. Key Concepts: Quinone cofactors are a class of cofactors used by many enzymes to catalyse the oxidation of amines and alcohols. Five quinone cofactors have been characterised: PQQ, TPQ, LTQ, TTQ and CTQ. PQQ is a peptide‐derived cofactor that involves the expression of six genes located within an operon. TPQ is derived from a precursor tyrosine and requires only Cu 2+ and O 2 for biogenesis. LTQ is formed by the cross‐linking of a tyrosine residue and a lysine residue, also requiring only Cu 2+ and O 2 . TTQ is formed by the cross‐linking of two tryprophan resides, with MauG completing biogenesis. CTQ, the most recently discovered quinone cofactor, is formed by the cross‐linking of a cysteine reside and a tryptophan residue.

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Vascular Adhesion Protein-1 Enhances Tumor Growth by Supporting Recruitment of Gr-1+CD11b+ Myeloid Cells into Tumors

Cited by 60 publications

References 44 publications

VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

Quinone Cofactors

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