The lymphatic vasculature in disease (original) (raw)
Schulte-Merker, S., Sabine, A. & Petrova, T.V. Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol.193, 607–618 (2011). ArticleCASPubMedPubMed Central Google Scholar
Pflicke, H. & Sixt, M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J. Exp. Med.206, 2925–2935 (2009). ArticleCASPubMedPubMed Central Google Scholar
Baluk, P. et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J. Clin. Invest.115, 247–257 (2005). ArticleCASPubMedPubMed Central Google Scholar
Dejana, E., Tournier-Lasserve, E. & Weinstein, B.M. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev. Cell16, 209–221 (2009). ArticleCASPubMed Google Scholar
Pfeiffer, F. et al. Distinct molecular composition of blood and lymphatic vascular endothelial cell junctions establishes specific functional barriers within the peripheral lymph node. Eur. J. Immunol.38, 2142–2155 (2008). ArticleCASPubMed Google Scholar
Tal, O., et al. DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J. Exp. Med.208, 2141–2153 (2011). ArticleCASPubMedPubMed Central Google Scholar
Norrmén, C., Tammela, T., Petrova, T.V. & Alitalo, K. Biological basis of therapeutic lymphangiogenesis. Circulation123, 1335–1351 (2011). ArticlePubMed Google Scholar
Karkkainen, M.J. et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol.5, 74–80 (2004). ArticleCASPubMed Google Scholar
Wigle, J.T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell98, 769–778 (1999). ArticleCASPubMed Google Scholar
Albrecht, I. & Christofori, G. Molecular mechanisms of lymphangiogenesis in development and cancer. Int. J. Dev. Biol.55, 483–494 (2011). ArticleCASPubMed Google Scholar
François, M. et al. Sox18 induces development of the lymphatic vasculature in mice. Nature456, 643–647 (2008). ArticleCASPubMed Google Scholar
Srinivasan, R.S. et al. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev.24, 696–707 (2010). ArticleCASPubMedPubMed Central Google Scholar
Mäkinen, T. et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev.19, 397–410 (2005). ArticlePubMedPubMed CentralCAS Google Scholar
Niessen, K. et al. The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development. Blood118, 1989–1997 (2011). ArticleCASPubMed Google Scholar
Zheng, W. et al. Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor. Blood118, 1154–1162 (2011). ArticleCASPubMed Google Scholar
Augustin, H.G., Koh, G.Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat. Rev. Mol. Cell Biol.10, 165–177 (2009). ArticleCASPubMed Google Scholar
Hogan, B.M. et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat. Genet.41, 396–398 (2009). ArticleCASPubMed Google Scholar
Bos, F.L. et al. CCBE1 Is Essential for Mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ. Res.109, 486–491 (2011). ArticleCASPubMed Google Scholar
Galvagni, F. et al. Endothelial cell adhesion to the extracellular matrix induces c-Src–dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity. Circ. Res.106, 1839–1848 (2010). ArticleCASPubMed Google Scholar
Tammela, T., et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat. Cell Biol.13, 1202–1213 (2011). ArticleCASPubMedPubMed Central Google Scholar
Uhrin, P. et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood115, 3997–4005 (2010). ArticleCASPubMed Google Scholar
Rasmussen, J.C., Tan, I.C., Marshall, M.V., Fife, C.E. & Sevick-Muraca, E.M. Lymphatic imaging in humans with near-infrared fluorescence. Curr. Opin. Biotechnol.20, 74–82 (2009). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Song, L., Maslov, K., Shung, K.K. & Wang, L.V. Ultrasound-array–based real-time photoacoustic microscopy of human pulsatile dynamics in vivo. J. Biomed. Opt.15, 021303 (2010). ArticlePubMedPubMed Central Google Scholar
Norrmén, C. et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J. Cell Biol.185, 439–457 (2009). ArticlePubMedPubMed CentralCAS Google Scholar
Kanady, J.D., Dellinger, M.T., Munger, S.J., Witte, M.H. & Simon, A.M. Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Dev. Biol.354, 253–266 (2011). ArticleCASPubMedPubMed Central Google Scholar
Mellor, R.H. et al. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation115, 1912–1920 (2007). ArticleCASPubMed Google Scholar
Bazigou, E. et al. Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. J. Clin. Invest.121, 2984–2992 (2011). ArticleCASPubMedPubMed Central Google Scholar
Ostergaard, P., et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat. Genet.43, 929–931 (2011). ArticleCASPubMed Google Scholar
Stanton, A.W., Modi, S., Mellor, R.H., Levick, J.R. & Mortimer, P.S. Recent advances in breast cancer-related lymphedema of the arm: lymphatic pump failure and predisposing factors. Lymphat. Res. Biol.7, 29–45 (2009). ArticlePubMed Google Scholar
McLaughlin, S.A. et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J. Clin. Oncol.26, 5213–5219 (2008). ArticlePubMedPubMed Central Google Scholar
Tammela, T. et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat. Med.13, 1458–1466 (2007). ArticleCASPubMed Google Scholar
Lähteenvuo, M. et al. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation123, 613–620 (2011). ArticleCASPubMed Google Scholar
Cormier, J.N., Rourke, L., Crosby, M., Chang, D. & Armer, J. The surgical treatment of lymphedema: a systematic review of the contemporary literature (2004–2010). Ann. Surg. Oncol. published online, doi:10.1245/s10434-011-2017-4 (24 August 2011).
Saaristo, A.M. et al. Microvascular breast reconstruction and lymph node transfer for postmastectomy lymphedema patients. Ann. Surg. (in the press).
Becker, C., Assouad, J., Riquet, M. & Hidden, G. Postmastectomy lymphedema: long-term results following microsurgical lymph node transplantation. Ann. Surg.243, 313–315 (2006). ArticlePubMedPubMed Central Google Scholar
Tammela, T. & Alitalo, K. Lymphangiogenesis: Molecular mechanisms and future promise. Cell140, 460–476 (2010). ArticleCASPubMed Google Scholar
Rissanen, T.T. et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ. Res.92, 1098–1106 (2003). ArticleCASPubMed Google Scholar
Anisimov, A. et al. Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circ. Res.104, 1302–1312 (2009). ArticleCASPubMedPubMed Central Google Scholar
Leppänen, V.M. et al. Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc. Natl. Acad. Sci. USA107, 2425–2430 (2010). ArticlePubMedPubMed Central Google Scholar
Kisko, K. et al. Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle X-ray solution scattering. FASEB J.25, 2980–2986 (2011). ArticleCASPubMed Google Scholar
Leppänen, V.M. et al. Structural determinants of vascular endothelial growth factor-D receptor binding and specificity. Blood117, 1507–1515 (2011). ArticleCASPubMed Google Scholar
Vondenhoff, M.F. et al. LTbetaR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen. J. Immunol.182, 5439–5445 (2009). ArticleCASPubMed Google Scholar
Vondenhoff, M.F. et al. Lymph sacs are not required for the initiation of lymph node formation. Development136, 29–34 (2009). ArticleCASPubMed Google Scholar
Förster, R., Davalos-Misslitz, A.C. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol.8, 362–371 (2008). ArticleCASPubMed Google Scholar
Wick, N. et al. Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am. J. Pathol.173, 1202–1209 (2008). ArticleCASPubMedPubMed Central Google Scholar
Pham, T.H. et al. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J. Exp. Med.207, 17–27 (2010). ArticleCASPubMedPubMed Central Google Scholar
Karikoski, M. et al. Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur. J. Immunol.39, 3477–3487 (2009). ArticleCASPubMed Google Scholar
Cohen, J.N. et al. Lymph node–resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med.207, 681–688 (2010). ArticleCASPubMedPubMed Central Google Scholar
Kang, S. et al. Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood113, 2605–2613 (2009). ArticleCASPubMed Google Scholar
Kataru, R.P. et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance and inflammation resolution. Blood113, 5650–5659 (2009). ArticleCASPubMed Google Scholar
Angeli, V. et al. B cell–driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity24, 203–215 (2006). ArticleCASPubMed Google Scholar
Kataru, R.P. et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity34, 96–107 (2011). ArticleCASPubMed Google Scholar
Cueni, L.N. & Detmar, M. The lymphatic system in health and disease. Lymphat. Res. Biol.6, 109–122 (2008). ArticlePubMed Google Scholar
von der Weid, P.Y., Rehal, S. & Ferraz, J.G. Role of the lymphatic system in the pathogenesis of Crohn's disease. Curr. Opin. Gastroenterol.27, 335–341 (2011). ArticleCASPubMed Google Scholar
Kerjaschki, D. et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat. Med.12, 230–234 (2006). ArticleCASPubMed Google Scholar
Nykänen, A.I. et al. Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation121, 1413–1422 (2010). ArticleCASPubMed Google Scholar
Albuquerque, R.J. et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat. Med.15, 1023–1030 (2009). ArticleCASPubMedPubMed Central Google Scholar
Yin, N. et al. Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation92, 25–30 (2011). ArticleCASPubMedPubMed Central Google Scholar
Lämmermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature453, 51–55 (2008). ArticlePubMedCAS Google Scholar
Miteva, D.O. et al. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res.106, 920–931 (2010). ArticleCASPubMed Google Scholar
Schumann, K. et al. Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity32, 703–713 (2010). ArticleCASPubMed Google Scholar
Johnson, L.A. & Jackson, D.G. Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. Int. Immunol.22, 839–849 (2010). ArticleCASPubMed Google Scholar
Bao, X. et al. Endothelial heparan sulfate controls chemokine presentation in recruitment of lymphocytes and dendritic cells to lymph nodes. Immunity33, 817–829 (2010). ArticleCASPubMedPubMed Central Google Scholar
Podgrabinska, S. et al. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1–dependent mechanism. J. Immunol.183, 1767–1779 (2009). ArticleCASPubMed Google Scholar
Vetrano, S. et al. The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6. Gut59, 197–206 (2010). ArticlePubMed Google Scholar
Gräbner, R. et al. Lymphotoxin Β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged _Apoe_−/− mice. J. Exp. Med.206, 233–248 (2009). ArticlePubMedPubMed CentralCAS Google Scholar
van de Pavert, S.A. & Mebius, R.E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol.10, 664–674 (2010). ArticleCASPubMed Google Scholar
Muniz, L.R., Pacer, M.E., Lira, S.A. & Furtado, G.C. A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. J. Immunol.187, 828–834 (2011). ArticleCASPubMed Google Scholar
Harvey, N.L. et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat. Genet.37, 1072–1081 (2005). ArticleCASPubMed Google Scholar
Rutkowski, J.M. et al. Dermal collagen and lipid deposition correlate with tissue swelling and hydraulic conductivity in murine primary lymphedema. Am. J. Pathol.176, 1122–1129 (2010). ArticleCASPubMedPubMed Central Google Scholar
Szuba, A. et al. Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J.16, 1985–1987 (2002). ArticleCASPubMed Google Scholar
Libby, P., Ridker, P.M. & Hansson, G.K. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol.54, 2129–2138 (2009). ArticleCASPubMedPubMed Central Google Scholar
Kholová, I. et al. Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions. Eur. J. Clin. Invest.41, 487–497 (2011). ArticlePubMed Google Scholar
Nakano, T. et al. Angiogenesis and lymphangiogenesis and expression of lymphangiogenic factors in the atherosclerotic intima of human coronary arteries. Hum. Pathol.36, 330–340 (2005). ArticleCASPubMed Google Scholar
Lim, H.Y. et al. Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration. Am. J. Pathol.175, 1328–1337 (2009). ArticleCASPubMedPubMed Central Google Scholar
Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism. Nat. Med.15, 545–552 (2009). ArticleCASPubMed Google Scholar
Wang, H.W. et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat. Genet.36, 687–693 (2004). ArticleCASPubMed Google Scholar
Cheng, F. et al. Virus-induced Notch-MT1-MMP axis leads to lymphatic endothelial-to-mesenchymal transition. Cell Host. Microbe (in the press).
Liu, R. et al. KSHV-induced notch components render endothelial and mural cell characteristics and cell survival. Blood115, 887–895 (2010). ArticleCASPubMedPubMed Central Google Scholar
Zhang, X. et al. Kaposi's sarcoma–associated herpesvirus activation of vascular endothelial growth factor receptor 3 alters endothelial function and enhances infection. J. Biol. Chem.280, 26216–26224 (2005). ArticleCASPubMed Google Scholar
Tvorogov, D. et al. Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization. Cancer Cell18, 630–640 (2010). ArticleCASPubMed Google Scholar
Harari, S., Torre, O. & Moss, J. Lymphangioleiomyomatosis: what do we know and what are we looking for? Eur. Respir. Rev.20, 34–44 (2011). ArticleCASPubMedPubMed Central Google Scholar
Seyama, K. et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat. Res. Biol.4, 143–152 (2006). ArticleCASPubMed Google Scholar
Fukumura, D., Duda, D.G., Munn, L.L. & Jain, R.K. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation17, 206–225 (2010). ArticleCASPubMedPubMed Central Google Scholar
Mumprecht, V. et al. In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography. Cancer Res.70, 8842–8851 (2010). ArticleCASPubMedPubMed Central Google Scholar
Leijte, J.A., van der Ploeg, I.M., Valdes Olmos, R.A., Nieweg, O.E. & Horenblas, S. Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J. Nucl. Med.50, 364–367 (2009). ArticlePubMed Google Scholar
Giuliano, A.E., et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. J. Am. Med. Assoc.306, 385–393 (2011). ArticleCAS Google Scholar
Louis-Sylvestre, C. et al. Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J. Clin. Oncol.22, 97–101 (2004). ArticlePubMed Google Scholar
Chaffer, C.L. & Weinberg, R.A. A perspective on cancer cell metastasis. Science331, 1559–1564 (2011). ArticleCASPubMed Google Scholar
Sleeman, J.P., Nazarenko, I. & Thiele, W. Do all roads lead to Rome? Routes to metastasis development. Int. J. Cancer128, 2511–2526 (2011). ArticleCASPubMed Google Scholar
Stoecklein, N.H. & Klein, C.A. Genetic disparity between primary tumours, disseminated tumour cells and manifest metastasis. Int. J. Cancer126, 589–598 (2010). ArticleCASPubMed Google Scholar
Shields, J.D., Kourtis, I.C., Tomei, A.A., Roberts, J.M. & Swartz, M.A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science328, 749–752 (2010). ArticleCASPubMed Google Scholar
Kim, M. et al. CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res.70, 10411–10421 (2010). ArticleCASPubMed Google Scholar
Madsen, C.D. & Sahai, E. Cancer dissemination—lessons from leukocytes. Dev. Cell19, 13–26 (2010). ArticleCASPubMed Google Scholar
Contassot, E., Preynat-Seauve, O., French, L. & Huard, B. Lymph node tumor metastases: more susceptible than primary tumors to CD8+ T cell immune destruction. Trends Immunol.30, 569–573 (2009). ArticleCASPubMed Google Scholar
Kerjaschki, D. et al. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J. Clin. Invest.121, 2000–2012 (2011). ArticleCASPubMedPubMed Central Google Scholar
Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature454, 656–660 (2008). ArticleCASPubMed Google Scholar
Roberts, N. et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res.66, 2650–2657 (2006). ArticleCASPubMed Google Scholar
Caunt, M. et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell13, 331–342 (2008). ArticleCASPubMed Google Scholar
Hooper, A.T. et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell4, 263–274 (2009). ArticleCASPubMedPubMed Central Google Scholar
Tammela, T. et al. Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. Sci. Transl. Med.3, 69ra11 (2011). ArticleCASPubMed Google Scholar
Goyal, S., Chauhan, S.K. & Dana, R. Blockade of prolymphangiogenic vascular endothelial growth factor C in dry eye disease. Arch. Ophthalmol. published online, doi:10.1001/archophthalmol.2011.266 (12 September 2011). ArticlePubMed Google Scholar
Koch, S., Tugues, S., Li, X., Gualandi, L. & Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Biochem. J.437, 169–183 (2011). ArticleCASPubMed Google Scholar
Saharinen, P. et al. Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development. Genes Dev.24, 875–880 (2010). ArticleCASPubMedPubMed Central Google Scholar
Yang, Y., Xie, P., Opatowsky, Y. & Schlessinger, J. Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling. Proc. Natl. Acad. Sci. USA107, 1906–1911 (2010). ArticleCASPubMedPubMed Central Google Scholar
Kendrew, J. et al. An antibody targeted to VEGFR-2 Ig domains 4–7 inhibits VEGFR-2 activation and VEGFR-2–dependent angiogenesis without affecting ligand binding. Mol. Cancer Ther.10, 770–783 (2011). ArticleCASPubMed Google Scholar
Koh, Y.J. et al. Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis and vascular leakage. Cancer Cell18, 171–184 (2010). ArticleCASPubMed Google Scholar
Hashizume, H. et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res.70, 2213–2223 (2010). ArticleCASPubMedPubMed Central Google Scholar
Brown, J.L. et al. A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models. Mol. Cancer Ther.9, 145–156 (2010). ArticleCASPubMed Google Scholar