Modalities of cell–cell communication of relevance to angiogenesis, inflammation and fibrosis include paracrine signalling, mechanosignalling, direct signal transduction via gap junctions and tunnelling nanotubes, and communication via the release and uptake of exosomes. Intercellular communication might be targeted by altering gap junctions and nanotubes, and exosomes are potential drug delivery vehicles as well as diagnostic markers.
Leukocytes interact with microvascular cells to affect angiogenesis. These interactions are potentially druggable processes for the regulation of angiogenesis.
Angiogenesis can occur through three different mechanisms — sprouting, intussusception and looping — which should be taken into account when designing new pharmacological treatments to reduce or increase angiongesis.
Different classes of leukocytes are potential targets to reduce uncontrolled fibrosis. Inhibited recruitment of inflammatory leukocytes together with on-site reprogramming of macrophages could promote fibrosis resolution.
In response to different signals from the environment, such as interferons, Toll-like receptor ligands or interleukins, macrophages undergo classical (M1) or alternative activation, which results in a continuum of diverse phenotypes depending on activation states. The identification of the underlying regulation of macrophage plasticity and polarized activation provides targets for macrophage-centred therapies.
Delineation of the endothelial heterogeneity is important to the development of strategies for the targeted delivery of drugs to organ-specific vascular beds to limit adverse effects.
Regulation of vascular permeability, recruitment of leukocytes from blood to tissue and angiogenesis are all processes that occur at the level of the microvasculature during both physiological and pathological conditions. The interplay between microvascular cells and leukocytes during inflammation, together with the emerging roles of leukocytes in the modulation of the angiogenic process, make leukocyte–vascular interactions prime targets for therapeutics to potentially treat a wide range of diseases, including pathological and dysfunctional vessel growth, chronic inflammation and fibrosis. In this Review, we discuss how the different cell types that are present in and around microvessels interact, cooperate and instruct each other, and in this context we highlight drug targets as well as emerging druggable processes that can be exploited to restore tissue homeostasis.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Three-dimensional vascular microenvironment landscape in human glioblastoma
Acta Neuropathologica Communications Open Access 12 February 2021
Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats
Biology of Sex Differences Open Access 15 January 2021
The secreted Ly6/uPAR-related protein-1 suppresses neutrophil binding, chemotaxis, and transmigration through human umbilical vein endothelial cells
Scientific Reports Open Access 11 April 2019
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).
Casazza, A. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013).
Christoffersson, G. et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 120, 4653–4662 (2012).
Chung, A. S. et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat. Med. 19, 1114–1123 (2013).
Ehling, J. et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63, 1960–1971 (2014).
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).
Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs. Nat. Immunol. 14, 41–51 (2013).
Hase, K. et al. M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nat. Cell Biol. 11, 1427–1432 (2009).
Kristensen, V. N. et al. Principles and methods of integrative genomic analyses in cancer. Nat. Rev. Cancer 14, 299–313 (2014).
Islam, S. et al. Quantitative single-cell RNA-seq with unique molecular identifiers. Nat. Meth. 11, 163–166 (2014).
Bentley, K. et al. The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis. Nat. Cell Biol. 16, 309–321 (2014).
Dejana, E., Tournier-Lasserve, E. & Weinstein, B. M. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev. Cell 16, 209–221 (2009).
Chauhan, V. P., Stylianopoulos, T., Boucher, Y. & Jain, R. K. Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu. Rev. Chem. Biomol. Eng. 2, 281–298 (2011).
Heldin, C. H., Rubin, K., Pietras, K. & Ostman, A. High interstitial fluid pressure — an obstacle in cancer therapy. Nat. Rev. Cancer 4, 806–813 (2004).
Conway, D. E. et al. Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr. Biol. 23, 1024–1030 (2013).
Tzima, E. et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426–431 (2005).
Langenkamp, E. & Molema, G. Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer. Cell Tissue Res. 335, 205–222 (2009).
Swift, M. R. & Weinstein, B. M. Arterial-venous specification during development. Circ. Res. 104, 576–588 (2009).
Lawson, N. D., Vogel, A. M. & Weinstein, B. M. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev. Cell 3, 127–136 (2002).
Wang, H. U., Chen, Z. F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).
D'Onofrio, N. et al. Vascular-homing peptides for targeted drug delivery and molecular imaging: meeting the clinical challenges. Biochim. Biophys. Acta 1846, 1–12 (2014).
Ageirsdottir, S. A. et al. Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium. Mol. Pharmacol. 72, 121–131 (2007). This study demonstrates means to direct drug delivery to specific organs and thereby limit systemic adverse effects by decorating exosomes with relevant adhesion molecules.
Ageirsdottir, S. A. et al. Inhibition of proinflammatory genes in anti-GB; glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes. Am. J. Renal Physiol. 294, F554–F561 (2008).
Corada, M. et al. Sox17 is indispensable for acquisition and maintenance of arterial identity. Nat. Commun. 4, 2609 (2013).
Fancy, S. P. et al. Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer. Nat. Neurosci. 17, 506–512 (2014).
Wu, B., Crampton, S. P. & Hughes, C. C. Wnt signaling induces matrix metalloproteinase expression and regulates T cell migration. Immunity 26, 227–239 (2007).
Jung, Y. S. et al. Wnt5a stimulates chemotactic migration and chemokine production in human neutrophils. Exp. Mol. Med. 45, e27 (2013).
Maiti, G., Naskar, D. & Sen, M. The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing. Proc. Natl Acad. Sci. USA 109, 16600–16605 (2012).
Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).
Gaengel, K. et al. The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2. Dev. Cell 23, 587–599 (2012). This study shows for the first time that sphingosine 1-phosphate (produced by, for example, platelets) is required for vessel maturation via the inhibition of VEGFA signalling and stabilization of VE-cadherin-based junctions.
Krueger, M. & Bechmann, I. CNS pericytes: concepts, misconceptions, and a way out. Glia 58, 1–10 (2010).
Sims, D. E. The pericyte — a review. Tissue Cell 18, 153–174 (1986).
Sims, D. E. Recent advances in pericyte biology — implications for health and disease. Can. J. Cardiol. 7, 431–443 (1991).
Falcón, B. L. et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol. 175, 2159–2170 (2009).
Gerhardt, H., Wolburg, H. & Redies, C. N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218, 472–479 (2000).
Wernersson, S. & Pejler, G. Mast cell secretory granules: armed for battle. Nat. Rev. Immunol. 14, 478–494 (2014).
Pollard, A. J., Perrett, K. P. & Beverley, P. C. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat. Rev. Immunol. 9, 213–220 (2009).
Fantin, A. et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829–840 (2010). This study demonstrates for the first time the role of tissue resident macrophages in vessel fusion in the developing brain.
Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).
Mantovani, A. Molecular pathways linking inflammation and cancer. Curr. Mol. Med. 10, 369–373 (2010).
Mantovani, A. & Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010).
Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).
Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology and health and disease. Nature 496, 445–455 (2013).
Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).
Armulik, A., Genové, G. & Betsholtz, C. Pericytes: development, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).
Wei, X. et al. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol. Sin. 34, 747–754 (2013).
Leeper, N. J., Hunter, A. L. & Cooke, J. P. Stem cell therapy for vascular regeneration. Circulation 122, 517–526 (2010).
Schinköthe, T., Bloch, W. & Schmidt, A. In vitro secreting profile of human mesenchymal stem cells. Stem Cells Dev. 17, 199–206 (2008).
Hsiao, S. T. et al. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose tissue, and dermal tissue. Stem Cells Dev. 21, 2189–2203 (2012).
Rustad, K. C. & Gurtner, G. C. Mesenchymal stem cells home to sites of injury and inflammation. Adv. Wound Care 1, 147–152 (2012).
Abram, C. L. & Lowell, C. A. The ins and outs of leukocyte integrin signaling. Annu. Rev. Immunol. 27, 339–362 (2009).
Fang, J. S., Dai, C., Kurjiaka, D. T., Burt, J. M. & Hirschi, K. K. Connexin45 regulates endothelial-induced mesenchymal cell differentiation toward a mural cell phenotype. Arterioscler. Thromb. Vasc. Biol. 33, 362–368 (2013).
Hirschi, K. K., Burt, J. M., Hirschi, K. D. & Dai, C. Gap junction communication mediates transforming growth factor-β activation and endothelial-induced mural cell differentiation. Circ. Res. 93, 429–437 (2003). This study shows that CX43 gap junction communication between endothelial cells and mesenchymal progenitors is necessary for the differentiation of progenitors into mural cells.
Westphalen, K. et al. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature 506, 503–506 (2014).
Mazzini, E., Massimiliano, L., Penna, G. & Rescigno, M. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 40, 248–261 (2014).
Oviedo-Orta, E., Errington, R. J. & Evans, W. H. Gap junction intercellular communication during lymphocyte transendothelial migration. Cell. Biol. Int. 26, 253–263 (2002).
Zahler, S. et al. Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration. J. Leuk. Biol. 73, 118–126 (2003).
Ghatnekar, G. S. et al. Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen. Med. 4, 205–223 (2009).
Grek, C. S., Rhett, J. M. & Ghatnekar, G. S. Cardiac to cancer: connecting connexins to clinical opportunity. FEBS Lett. 588, 1349–1364 (2014).
Ghatnekar, G. S., Grek, C. L., Armstrong, D. G., Desai, S. C. & Gourdie, R. G. The effect of a connexin43-based peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial. J. Invest. Dermatol. 135, 289–298 (2015).
van Balkom, B. W. et al. Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 121, 3997–4006 (2013).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).
Patzelt, J. & Langer, H. F. Platelets in angiogenesis. Curr. Vasc. Pharmacol. 10, 570–577 (2012).
Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).
Battinelli, E. M., Markens, B. A. & Italiano, J. E. Jr. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 118, 1359–1369 (2011).
Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotech. 29, 341–345 (2011). This study presents evidence that exosomes from self-derived dendritic cells, engineered to express the neuron-specific rabies viral glycoprotein (RVG) peptide, can selectively deliver functional siRNA to distinct cell populations in the brain.
Zech, D., Sanyukta, R., Büchler, M. W. & Xöller, M. Tumor-crosstalk and leukocyte activation: an ambivalent crosstalk. Cell Comm. Signal. 10, 37 (2012).
Marleau, A. M., Chen, C. S., Joyce, J. A. & Tullis, R. H. Exosome removal as a therapeutic adjuvant in cancer. J. Transl. Med. 10, 134 (2012).
Lu, H. et al. Exo70 isoform switching upon epithelial–mesenchymal transition mediates cancer cell invasion. Dev. Cell 27, 560–573 (2013).
Zhao, Y. et al. Exo70 generates membrane curvature for morphogenesis and cell migration. Dev. Cell 26, 266–278 (2013).
Chacon-Heszele, M. F. et al. The exocyst and regulatory GTPases in urinary exosomes. Physiol. Rep. 2, e12116 (2014).
Lou, E. et al. Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS ONE 7, e33093 (2012).
Ahmad, T. et al. Miro1 regulates intercellular mitochondrial transport and enhances mesenchymal stem cell rescue efficacy. EMBO J. 33, 994–1010 (2014).
Chen, L., Yang, S., Jakoncic, J., Zhang, J. J. & Huang, X. Y. Migrastatin analogues target fascin to block tumour metastasis. Nature 464, 1062–1066 (2010).
Pasquier, J. et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J. Transl. Med. 11, 94 (2013).
Rainy, N. et al. H-Ras transfers from B to T cells via tunneling nanotubes. Cell Death Dis. 4, e726 (2013).
Yasuda, K. et al. Tunneling nanotubes mediate rescue of prematurely senescent endothelial cells by endothelial progenitors: exchange of lysosomal pool. Aging 3, 597–608 (2011).
Liu, K. et al. Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc. Res. 92, 10–18 (2014).
Claesson-Welsh, L. & Welsh, M. VEGFA and tumour angiogenesis. J. Intern. Med. 273, 114–127 (2013).
Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).
Adams, R. H. & Alitalo, K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat. Rev. Mol. Cell. Biol. 8, 464–478 (2007).
Styp-Rekowska, B., Hlushchuk, R., Pries, A. R. & Djonov, V. Intussusceptive angiogenesis: pillars against the blood flow. Acta Physiol. (Oxf.) 202, 213–223 (2011).
Adams, R. H. & Eichmann, A. Axon guidance molecules in vascular patterning. Cold Spring Harb. Perspect. Biol. 2, a001875 (2010).
Jakobsson, L., Kreuger, J. & Claesson-Welsh, L. Building blood vessels-stem cell models in vascular biology. J. Cell Biol. 177, 751–755 (2007).
Lander, A. D. How cells know where they are. Science 339, 923–927 (2013).
Benest, A. V. & Augustin, H. G. Tension in the vasculature. Nat. Med. 15, 608–610 (2009).
Boerckel, J. D., Uhrig, B. A., Willett, N. J., Huebsch, N. & Guldberg, R. E. Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc. Natl Acad. Sci. USA 108, E674–E680 (2011).
Kilarski, W. W., Samolov, B., Petersson, L., Kvanta, A. & Gerwins, P. Biomechanical regulation of blood vessel growth during tissue vascularization. Nat. Med. 15, 657–664 (2009). This study demonstrates that during wound healing activated myofibroblasts generate mechanical forces that rapidly pull and elongate vessels from intact vascular beds into the wounded area. The vascular network is thereafter modulated by sprouting, splitting and regression.
Vakoc, B. J. et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat. Med. 15, 1219–1223 (2009).
Tabe, Y. et al. TGF-β-neutralizing antibody 1D11 enhances cytarabine-induced apoptosis in AML cells in the bone marrow microenvironment. PLoS ONE 8, e62785 (2011).
Dituri, F. et al. Differential inhibition of the TGF-β signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-β receptor type II. PLoS ONE 8, e67109 (2013).
Santiago, B. et al. Topical application of a peptide inhibitor of transforming growth factor-β1 ameliorates bleomycin-induced skin fibrosis. J. Invest. Dermatol. 125, 450–455 (2005).
Khalil, N., Bereznay, O., Sporn, M. & Greenberg, A. H. Macrophage production of transforming growth factor β and fibroblast collagen synthesis in chronic pulmonary inflammation. J. Exp. Med. 170, 727–737 (1989).
Nacu, N. et al. Macrophages produce TGF-β-induced (β-ig-h3) following ingestion of apoptotic cells and regulate MMP14 levels and collagen turnover in fibroblasts. J. Immunol. 180, 5036–5044 (2008).
Taichman, N. S., Young, S., Cruchley, A. T., Taylor, P. & Paleoplog, E. Human neutrophils secrete vascular endothelial growth factor. J. Leuk. Biol. 62, 397–400 (1997).
Auffray, C. et al. Monitoring of blood vessels and tissue by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).
Awojoodu, A. O. et al. Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis. Proc. Natl Acad. Sci. USA 110, 13785–13790 (2013).
Carlin, L. M. et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).
Ganju, R. K. et al. The α-chemokine, stromal cell-derived factor-1α, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J. Biol. Chem. 273, 23169–23175 (1998).
Grunewald, M. et al. VEGF-induced adult neovascuarisation, recruitment, retention and role of accessory cells. Cell 124, 175–189 (2006).
Avraham-Davidi, I. et al. On-site education of VEGF-recruited monocytes improves their performance as angiogenesis and arteriogenic accessory cells. J. Exp. Med. 210, 2611–2625 (2013). This study demonstrates that local VEGF 're-educates' monocytes to attain a pro-angiogenic phenotype.
Christoffersson, G. et al. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes 59, 2569–2578 (2010).
Massena, S. et al. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1 and CXCR4 in mice and humans. Blood 126, 2016–2026 (2015).
Kerbel, R. S. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 13, 31–36 (1991).
Lim, L. S., Mitchell, P., Seddon, J. M., Holz, F. G. & Wong, T. Y. Age-related macular degeneration. Lancet 379, 1728–1738 (2012).
Reck, M. et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J. Clin. Oncol. 27, 1227–1234 (2009).
Saltz, L. B. et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized Phase III study. J. Clin. Oncol. 26, 2013–2019 (2008).
Sandler, A. et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).
Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human renal cancer. Nat. Med. 10, 145–147 (2004).
Batchelor, T. T. et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc. Natl Acad. Sci. USA 47, 19059–19064 (2013).
Armstrong, T. S., Wen, P. Y., Gilbert, M. R. & Schiff, D. Management of treatment-associated toxicites of anti-angiogenic therapy in patients with brain tumors. Neuro. Oncol. 14, 1203–1214 (2012).
Wu, J. M. & Staton, C. A. Anti-angiogenic drug discovery: lessons from the past and thoughts for the future. Expert Opin. Drug Discov. 7, 723–743 (2012).
Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).
Barone, A. et al. Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma. Oncotarget 5, 9811–9822 (2014). In a mouse model of glioblastoma, this study shows that angiogenesis, tumour growth and metastasis are reduced by treatment with the CXCR4 inhibitor CTCE-9908 in combination with docetaxel or a VEGF-specific antibody.
Hassan, S. et al. CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. Int. J. Cancer 129, 225–232 (2011).
Pan, Q. et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11, 53–67 (2007).
Ruan, G.-X. & Kazlauskas, A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. J. Biol. Chem. 288, 21161–21172 (2013).
De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013). This study demonstrates that loss of the glycolytic activator PFKFB3 in endothelial cells results in impaired angiogenesis. PFKFB3 is required for proliferation but also regulates filopodia formation and chemotaxis.
Leopold, J. A. et al. Glucose-6-phosphate dehydrogenase modulates vascular endothelial growth factor-mediated angiogenesis. J. Biol. Chem. 278, 32100–32106 (2003).
Schoors, S. et al. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell. Metab. 19, 37–48 (2014).
Leite de Oliveira, R. et al. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell 22, 263–277 (2012).
Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).
Takeda, Y. et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479, 122–126 (2011).
Hamm, A. et al. PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Mol. Med. 5, 843–857 (2013).
Flagg, S. C., Martin, C. B., Taabazuing, C. Y., Holmes, B. E. & Knapp, M. J. Screening chelating inhibitors of HIF–prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH). J. Inorg. Biochem. 113, 25–30 (2012).
Hellström, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).
Phng, L. K. et al. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev. Cell 16, 70–82 (2009).
Dimova, I. et al. Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells. Angiogenesis 16, 921–937 (2013).
Outtz, H. H., Tattersall, I. W., Kofler, N. M., Steinbach, N. & Kitajewski, J. Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118, 3436–3439 (2011).
Camelo, S. et al. Delta-like 4 inhibits choroidal neovascularization despite opposing effects on vascular endothelium and macrophages. Angiogenesis 15, 609–622 (2012).
Haj Zen, A. A. et al. Inhibition of delta-like-4-mediated signaling impairs reparative angiogenesis after ischemia. Circ. Res. 107, 283–293 (2010).
Wang, Y. C. et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70, 4840–4849 (2010).
Xu, H. et al. Notch–RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat. Immunol. 13, 642–650 (2012).
Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–819 (2008).
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).
Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).
Stefater, J. A. 3rd et al. Regulation of angiogenesis by a non-canonical Wnt–Flt1 pathway in myeloid cells. Nature 474, 511–515 (2011).
Stefater, J. A. 3rd et al. Macrophage Wnt–Calcineurin–Flt1 signaling regulates mouse wound angiogenesis and repair. Blood 121, 2574–2578 (2013).
Ross, K. For organ transplant recipients, cancer threatens long-term survival. J. Nat. Cancer Inst. 99, 421–422 (2007).
Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).
Nourshargh, S., Hordijk, P. L. & Sixt, M. Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nat. Rev. Mol. Cell. Biol. 11, 366–378 (2010).
Phillipson, M. & Kubes, P. The neutrophil in vascular inflammation. Nat. Med. 17, 1381–1390 (2011).
Luo, B. H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).
Massena, S. et al. A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils. Blood 116, 1924–1931 (2010). This study demonstrates that an intravascular chemokine gradient on endothelial heparan sulfate directs crawling neutrophils towards the site of chemokine origin and accelerates their transmigration.
Phillipson, M. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J. Exp. Med. 203, 2569–2575 (2006).
Schenkel, A. R., Mamdouh, Z. & Muller, W. A. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat. Immunol. 5, 393–400 (2004).
Voisin, M. B., Pröbstl, D. & Nourshargh, S. Venular basement membranes ubiquitously express matrix protein low-expression regions: characterization in multiple tissues and remodeling during inflammation. Am. J. Pathol. 176, 482–495 (2010).
Wang, S. et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J. Exp. Med. 203, 1519–1532 (2006).
Carman, C. V. & Springer, T. A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377–388 (2004).
Petri, B. et al. Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo. Blood 117, 942–952 (2011).
Phillipson, M., Kaur, J., Colarusso, P., Ballantyne, C. M. & Kubes, P. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration. PLoS ONE 3, e1649 (2008).
Liu, L. et al. LSP1 is an endothelial gatekeeper of leukocyte transendothelial migration. J. Exp. Med. 201, 409–418 (2005).
Broermann, A. et al. Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo. J. Exp. Med. 208, 2393–2401 (2011).
Finsterbusch, M., Voisin, M. B., Beyrau, M., Williams, T. J. & Nourshargh, S. Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF. J. Exp. Med. 211, 1307–1314 (2014).
Proebstl, D. et al. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J. Exp. Med. 209, 1219–1234 (2012). This study demonstrates that pericytes support neutrophil migration to inflamed tissue by providing a surface for neutrophil crawling and by enlarging the inter-pericyte spaces by contraction.
Abtin, A. et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat. Immunol. 15, 45–53 (2014). This study shows that perivascular macrophages guide neutrophil extravasation and comprise targets during bacterial immune evasion.
Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).
Fox, D. A. Kinase inhibition — a new approach to the treatment of rheumatoid arthritis. N. Engl. J. Med. 367, 565–567 (2012).
Hoepner, R., Faissner, S., Salmen, A., Gold, R. & Chan, A. Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis. J. Cent. Nerv. Syst. Dis. 6, 41–49 (2014).
Kothary, N. et al. Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients. J. Am. Acad. Dermatol. 65, 546–551 (2011).
Schwab, N. et al. Fatal PML associated with efalizumab therapy: insights into integrin αLβ2 in JC virus control. Neurology 78, 458–467 (2012).
Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N. Engl. J. Med. 353, 362–368 (2005).
Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Eng. J. Med. 369, 699–710 (2013). In this clinical study, the beneficial effect of integrin-specific antibody therapy targeting α4β7 in patients with ulcerative colitis is demonstrated.
Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Eng. J. Med. 369, 711–721 (2013).
Briskin, M. et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97–110 (1997).
Danese, S. & Panés, J. Development of drugs to target interactions between leukocytes and endothelial cells and treatment algorithms for inflammatory bowel diseases. Gastroenterology 147, 981–989 (2014).
Fedyk, E. R. et al. Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates. Inflamm. Bowel. Dis. 18, 2107–2119 (2012).
Haanstra, K. G. et al. Antagonizing the α4β1 integrin, but not α4β7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis. J. Immunol. 190, 1961–1973 (2013).
Milch, C. et al. Vedolizumab, a monoclonal antibody to the gut homing α4β7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype. J. Neuroimmunol. 264, 123–126 (2013).
Watanabe, M. et al. 370 AJM300, an oral α4 integrin antagonist, for active ulcerative colitis: a multicenter, randomized, double-blind, placebo-controlled Phase 2A study. Gastroenterology 146, S-82 (2014).
Economides, A. N. et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat. Med. 9, 47–52 (2003).
Blanchetot, C. et al. Neutralizing nanobodies targeting diverse chemokines effectively inhibit chemokine function. J. Biol. Chem. 288, 25173–25182 (2013).
Berghmans, N. et al. Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes. J. Neuroinfl. 9, 243 (2012).
Li, S. et al. Interference with glycosaminoglycan-chemokine interactions with a probe to alter leukocyte recruitment and inflammation in vivo. PLoS ONE 9, e104107 (2014).
Klarenbeek, A. et al. Targeting chemokines and chemokine receptors with antibodies. Drug Discov. Today Tech. 9, 237–244 (2012).
Perry, C. M. Maraviroc: a review of its use in the management of CCR5-tropic HIV-1 infection. Drugs 70, 1189–1213 (2010).
De Clercq, E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem. Pharmacol. 77, 1655–1664 (2009).
Moelants, E. A. et al. Citrullination of TNF-α by peptidylarginine deiminases reduces its capacity to stimulate the production of inflammatory chemokines. Cytokine 61, 161–167 (2013).
Proost, P. et al. Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation. J. Exp. Med. 205, 2085–2097 (2008). This study demonstrates that inflammation can be regulated by post-translational modifications of chemokines to greatly affect chemokine activity and stability.
Moelants, E. A. et al. Citrullination and proteolytic processing of chemokines by Porphyromonas gingivalis. Infect. Immun. 82, 2511–2519 (2014).
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185 (2013).
Korns, D., Frasch, S. C., Fernandez-Boyanapalli, R., Henson, P. M. & Bratton, D. L. Modulation of macrophage efferocytosis in inflammation. Front. Immunol. 2, 57 (2011).
Markworth, J. F. et al. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R1281–R1296 (2013).
Colas, R. A., Shinohara, M., Dalli, J., Chiang, N. & Serhan, C. N. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am. J. Physiol. Cell Physiol. 307, C39–C54 (2014). This study identifies the mediators involved in resolution of acute inflammation, including lipoxins, resolvins, protectins and maresins in human plasma and lymphoid organs.
Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).
Jin, Y. et al. Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators. Invest. Ophthalmol. Vis. Sci. 50, 4743–4752 (2009).
Rajasagi, N. K. et al. Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1. J. Immunol. 186, 1735–1746 (2011).
Tang, Y. et al. Proresolution therapy for the treatment of delayed healing of diabetic wounds. Diabetes 62, 618–627 (2013).
Wu, S. H., Chen, X. Q., Liu, B., Wu, H. J. & Dong, L. Efficacy and safety of 15(R/S)-methyl-lipoxin A4 in topical treatment of infantile eczema. Br. J. Dermatol. 168, 172–178 (2013).
Robertson, A. L. et al. A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism. Sci. Transl. Med. 6, 225ra29 (2014).
Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound heling in solid organs. Nat. Rev. Immunol. 14, 181–194 (2014).
Moustakas, A. & Heldin, P. TGFβ and matrix regulated epithelial to mesenchymal transition. Biochim. Biophys. Acta 1840, 2621–2634 (2014).
Brenner, D. A. et al. Origin of myofibroblasts in liver fibrosis. Fibrogen. Tissue Repair 5, S17 (2012).
Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807–1816 (2007).
Henderson, N. C. et al. Targeting of αV integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013). Depletion of αV integrin in mouse hepatic stellate cells was shown to protect against fibrosis in several organs. The authors suggest that pharmacological targeting of αV integrin may be of broad clinical utility.
Thiery, J. P., Acloque, H., Huang, R. Y. J. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Cenik, B. K., Ostapoff, K. T., Gerber, D. E. & Brekken, R. A. BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol. Cancer Ther. 12, 992–1001 (2013).
Mehal, W. Z., Iredale, J. & Friedman, S. L. Scraping fibrosis: expressway to the core of fibrosis. Nat. Med. 17, 552–553 (2011).
Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).
Subramaniam, N. et al. Metformin-mediated BAMBI expression in hepatic stellate cells induces prosurvival Wnt/β catenin signaling. Cancer Prev. Res. 5, 553–561 (2012).
Ogawa, S. et al. Anti-PDGF-B monoclonal antibody reduces liver fibrosis development. Hepatol. Res. 40, 1128–1141 (2010).
Coulon, S. et al. Role of vascular endothelial growth factor in the pathophysiology of nonalcoholic steatohepatitis in two rodent models. Hepatology 57, 1793–19805 (2013).
Ardi, V. C., Kupriyanova, T. A., Deryugina, E. I. & Quigley, J. P. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc. Natl Acad. Sci. USA 104, 20262–20267 (2007).
Purcell, B. P. et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat. Mater. 13, 653–661 (2014).
Bystrom, J. et al. Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. Blood 112, 4117–4127 (2008).
Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012). This paper describes the first identification and characterization of the 'restorative macrophage', which can promote tissue remodelling and resolution of fibrosis.
Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell. Biol. 153, 543–553 (2001).
Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).
Lindahl, P., Johansson, B. R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).
Kelly-Goss, M. R., Sweat, R. S., Stapor, P. C., Peirce, S. M. & Murfee, W. L. Targeting pericytes for angiogenic therapies. Microcirculation 21, 345–357 (2014).
Ayres-Sander, C. E. et al. Transendothelial migration enables subsequent transmigration of neutrophils through underlying pericytes. PLoS ONE 8, e60025 (2013).
Ren, S. et al. LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1. Proc. Natl Acad. Sci. USA 110, 1440–1445 (2013).
Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).
Lee, W. Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat. Immunol. 11, 295–302 (2010).
Chintalgattu, V. et al. Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity. Sci. Transl. Med. 5, 187ra69 (2013).
Ehnman, M. et al. Distinct effects of ligand-induced PDGFRα and PDGFRβ signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. Cancer Res. 73, 2139–2149 (2013).
Ruan, J. et al. Imatinin disrupts lymphoma angiogenesis by targeting vascular pericytes. Blood 121, 5192–5202 (2013).
Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 15, 143–155 (2014).
Purow, B. Notch inhibition as a promising new approach to cancer therapy. Adv. Exp. Med. Biol. 727, 305–319 (2012).
Sun, L. et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl- 1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 46, 1116–1119 (2003).
Roberts, W. G. et al. Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. Cancer Res. 65, 957–966 (2005).
Wilhelm, S. M. et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004).
Laird, A. D. et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152–4160 (2000).
Pan, B. S. et al. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 70, 1524–1533 (2010).
Albert, D. H. et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Can. Therap. 5, 995–1006 (2006).
Hu-Lowe, D. D. et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin. Cancer Res. 14, 7272–7283 (2008).
Buchdunger, E. et al. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Proc. Natl Acad. Sci. USA 92, 2558–2562 (1995).
Heinrich, M. C. et al. Inhibition of c-KIT receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925–932 (2000).
Heinrich, M. C. et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin. Cancer Res. 18, 4375–4384 (2012).
Trudel, S. et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105, 2941–2948 (2005).
Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008).
Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Allavena, P. et al. Intraperitoneal recombinant gamma-interferon in patients with recurrent ascitic ovarian carcinoma: modulation of cytotoxicity and cytokine production in tumor-associated effectors and of major histocompatibility antigen expression on tumor cells. Cancer Res. 50, 7318–7323 (1990).
Krieg, A. M. Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471–484 (2006).
Sun, Z., Yao, Z., Liu, S., Tang, H. & Yan, X. An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer. Immunobiology 211, 199–209 (2006).
Hemmi, H. et al. Small anti-viral compounds activate the immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200 (2002).
Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).
Freemerman, A. J. et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289, 7884–7896 (2014).
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).
Lutgens, E. et al. Deficient CD40–TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J. Exp. Med. 207, 391–404 (2010).
Kurowska-Stolarska, M. et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J. Immunol. 183, 6469–6499 (2009).
Germano, G. et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res. 70, 2235–2244 (2010).
The authors would like to thank the members of their laboratories and many of their colleagues, especially L. Claesson-Welsh, A. Moustakas and M. Welsh for sharing their insights and for stimulating discussions. The authors apologize to all colleagues whose relevant work has not been cited owing to space limitations. The authors are supported by the Swedish Medical Research Council, the Swedish Cancer Society, the Royal Swedish Academy of Sciences, the Swedish Diabetes Foundation, the Swedish Foundation for Strategic Research, the Novo Nordisk Foundation, the Ragnar Söderberg foundation, the Knut and Alice Wallenberg Foundation, the Ruth and Nils-Erik Stenbäcks Foundation, the Foundations for Proteoglycan Research, the Marie Sklodowska-Curie Innovative Training Network InCeM (Integrated Component Cycling in Epithelial Cell Motility) and Uppsala University.
The authors declare no competing financial interests.
White blood cells of the immune system. Different classes of leukocytes may fight infections or modulate processes such as angiogenesis, inflammation and fibrosis.
- Mural cells
The vascular smooth muscle cells and pericytes that surround and support endothelial cells.
- Tunnelling nanotubes
Very thin cytoplasmic extensions containing actin that connect various cell types to allow direct exchange of intracellular components.
- Intravital microscopy
A microscopy technique that enables direct observations of biological processes in vivo.
Emigration of immune cells from the vasculature into the surrounding tissue.
Antibody-conjugated spheres of phospholipids that can be used to deliver drugs to tissues.
- Alternatively activated macrophages
These macrophages are less efficient at killing bacteria and are activated by different cytokines than are the classic M1 inflammatory macrophages. Alternatively activated macrophages are involved in tissue remodelling, wound healing, angiogenesis and tumour progression.
- Inside-out signalling
Leukocyte integrin inside-out signalling occurs following chemokine receptor ligation and activates the ligand-binding function of the integrins.
- Outside-in signalling
Integrin outside-in signalling occurs following the binding of leukocyte integrins to their counter-receptors on the endothelium and results in cytoskeletal rearrangements, strengthening of adhesion, cell spreading and migration.
- Epithelial–mesenchymal transition
A process in which normally stationary epithelial cells lose cell–cell adhesions and cell polarity, thus becoming migratory.
Rights and permissions
About this article
Cite this article
Kreuger, J., Phillipson, M. Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis. Nat Rev Drug Discov 15, 125–142 (2016). https://doi.org/10.1038/nrd.2015.2
This article is cited by
Design of therapeutic biomaterials to control inflammation
Nature Reviews Materials (2022)
Prediction of the Postoperative Fat Volume Retention Rate After Augmentation Mammoplasty with Autologous Fat Grafting: From the Perspective of Preoperative Inflammatory Level
Aesthetic Plastic Surgery (2022)
Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats
Biology of Sex Differences (2021)
Three-dimensional vascular microenvironment landscape in human glioblastoma
Acta Neuropathologica Communications (2021)
The secreted Ly6/uPAR-related protein-1 suppresses neutrophil binding, chemotaxis, and transmigration through human umbilical vein endothelial cells
Scientific Reports (2019)