VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice

Abstract

Key Points• Metastatic tumor cell attachment induces endothelial VCAM-1 and VAP-1.• VCAM-1 and VAP-1 promote metastatic tumor cell survival by recruiting myeloid cells, pointing to VAP-1 as a therapeutic target.Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis. (Blood. 2013;121(16):3289-3297)

Intravital imaging reveals distinct responses of depleting dynamic tumor-associated macrophage and dendritic cell subpopulations

“…Macrophage and monocyte populations have been reported to support the seeding of metastatic breast cancer cells in the lung, assisting their extravasation, secreting vascular endothelial growth factor and inducing angiogenesis, and they also promote the growth of metastatic lesions (12,13,41,42,53,54). Macrophages support tumor cell migration and invasiveness by secreting chemotactic epithelial growth factor and matrix-remodeling proteases, such as cathepsins and MMPs (55)(56)(57)(58).…”

miR‑126/VCAM‑1 regulation by naringin suppresses cell growth of human non‑small cell lung cancer

“…VCAM-1 was activated by inflammation (8). In addition, it is also expressed in dendritic cells, including macrophages and placental trophoblastic cells, B-lymphocytes, smooth muscle cells, fibroblast cells and certain epithelial cells of the kidney (28).…”

“…The invasion and metastases of malignant tumors are complicated biological phenomena, in which cell adhesion serves a vital role (8). VCAM-1 was activated by inflammation (8).…”

“…An adhesion molecule is a bio-macromolecule that mediates the binding between cells, and between cells and the extracellular matrix, and serves an important role in maintaining the normal structures of tissues and homeostasis of various pathophysiological processes including the inflammatory and immune responses, blood coagulation, formation of thrombosis and the invasion and metastasis of malignant tumors (8). Based on their structures, adhesion molecules may be grouped into various families: The integrin family, selectin family, immunoglobulin superfamily, E-cadherin family and other families, among which intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are the most important types, and serve vital roles in regulating the binding between cells, and between cells and the extracellular matrix (9).…”

PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

“…Issues such as poor cross-species potency, unsuitable physicochemical properties, selectivity, and inherent class-based toxicity or off-target activity have proven to be a significant hurdle to drug development. For example, PRX.A, an inhibitor thought to be structurally related to compound 6, exhibited nanomolar potency against the mouse enzyme and was efficacious in a murine model of pulmonary metastasis (Ferjan ci c et al, 2013); however, this molecule also had undesirable off-target activity against human dopamine transporter and Na 1 channel proteins at 1 mM. In addition, PXS-4681A, an Improved SSAO Inhibitor with In Vivo Activity Inoue et al (2013a,b,c) documented the development of compound 7, which showed efficacy in a rat streptozotocin-induced ocular permeability model but suffered from poor pharmacodynamic coverage (see below).…”