Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? (original) (raw)

• Crawford, Y. & Ferrara, N. VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res. 335, 261–269 (2009).
  Article CAS PubMed Google Scholar
• Fraisl, P., Mazzone, M., Schmidt, T. & Carmeliet, P. Regulation of angiogenesis by oxygen and metabolism. Dev. Cell 16, 167–179 (2009).
  Article CAS PubMed Google Scholar
• Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Schomber, T. et al. Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol. Cancer Ther. 8, 55–63 (2009).
  Article CAS PubMed Google Scholar
• Padera, T. P. et al. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Ther. 7, 2272–2279 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, D. X., Bos, P. D. & Massagué, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274–284 (2009).
  Article CAS PubMed Google Scholar
• Rundqvist, H. & Johnson, R. S. Hypoxia and metastasis in breast cancer. Curr. Top. Microbiol. Immunol. 345, 121–139 (2010).
  CAS PubMed Google Scholar
• Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010).
  Article CAS PubMed Google Scholar
• Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Madsen, C. D. & Sahai, E. Cancer dissemination–lessons from leukocytes. Dev. Cell 19, 13–26 (2010).
  Article CAS PubMed Google Scholar
• Friedl, P. & Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nat. Rev. Mol. Cell Biol. 10, 445–457 (2009).
  Article CAS PubMed Google Scholar
• Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).
  Article CAS PubMed Google Scholar
• Yilmaz, M. & Christofori, G. Mechanisms of motility in metastasizing cells. Mol. Cancer Res. 8, 629–642 (2010).
  Article CAS PubMed Google Scholar
• Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
  Article CAS PubMed Google Scholar
• Friedl, P. & Wolf, K. Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res. 68, 7247–7249 (2008).
  Article CAS PubMed Google Scholar
• Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007).
  Article CAS PubMed Google Scholar
• Haase, V. H. Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int. 76, 492–499 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, X. & Kang, Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin. Cancer Res. 16, 5928–5935 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Eltzschig, H. K. & Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med. 364, 656–665 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Erler, J. T. & Giaccia, A. J. Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res. 66, 10238–10241 (2006).
  Article CAS PubMed Google Scholar
• Franovic, A. et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc. Natl Acad. Sci. USA 104, 13092–13097 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Petrella, B. L. & Brinckerhoff, C. E. PTEN suppression of YY1 induces HIF-2 activity in von-Hippel-Lindau-null renal-cell carcinoma. Cancer Biol. Ther. 8, 1389–1401 (2009).
  Article CAS PubMed Google Scholar
• Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Yoo, Y. G., Kong, G. & Lee, M. O. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J. 25, 1231–1241 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Paulis, Y. W., Soetekouw, P. M., Verheul, H. M., Tjan-Heijnen, V. C. & Griffioen, A. W. Signalling pathways in vasculogenic mimicry. Biochim. Biophys. Acta 1806, 18–28 (2010).
  CAS PubMed Google Scholar
• Fidler, I. J. The role of the organ microenvironment in brain metastasis. Semin. Cancer Biol. 21, 107–112 (2011).
  Article PubMed Google Scholar
• Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol. 2, 251–275 (2007).
  Article CAS PubMed 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).
  Article CAS PubMed Google Scholar
• Du, R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, R. Z. et al. Tumor-induced endothelial cell apoptosis: roles of NAD(P)H oxidase-derived reactive oxygen species. J. Cell. Physiol. 226, 1750–1762 (2011).
  Article CAS PubMed Google Scholar
• Gaengel, K., Genové, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).
  Article CAS PubMed Google Scholar
• Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kallergi, G. et al. Hypoxia-inducible factor-1α and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res. 11, R84 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Rohwer, N. et al. Hypoxia-inducible factor 1α mediates anoikis resistance via suppression of α5 integrin. Cancer Res. 68, 10113–10120 (2008).
  Article CAS PubMed Google Scholar
• Jokilehto, T. et al. Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth. Exp. Cell Res. 316, 1169–1178 (2010).
  Article CAS PubMed Google Scholar
• Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Duda, D. G. et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl Acad. Sci. USA 107, 21677–21682 (2011).
  Article Google Scholar
• Chiavarina, B. et al. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle 9, 3534–3551 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, M. P., Park, S. I., Kopetz, S. & Gallick, G. E. Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasis. Cell Tissue Res. 335, 249–259 (2009).
  Article CAS PubMed 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. Cell 16, 209–221 (2009).
  Article CAS PubMed Google Scholar
• Koike, T. et al. Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates. Proc. Natl Acad. Sci. USA 101, 8132–8137 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Le Jan, S. et al. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am. J. Pathol. 162, 1521–1528 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Falanga, V. et al. Hypoxia upregulates the synthesis of TGF-beta 1 by human dermal fibroblasts. J. Invest. Dermatol. 97, 634–637 (1991).
  Article CAS PubMed Google Scholar
• Huang, Y. et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009).
  Article CAS PubMed Google Scholar
• Hiratsuka, S. et al. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc. Natl Acad. Sci. USA 108, 3725–3730 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).
  Article PubMed PubMed Central Google Scholar
• Schmidt, T. et al. Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1+ leukemia. Cancer Cell (in press).
• Horak, C. E., Lee, J. H., Marshall, J. C., Shreeve, S. M. & Steeg, P. S. The role of metastasis suppressor genes in metastatic dormancy. APMIS 116, 586–601 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 7, 834–846 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Hedley, B. D. & Chambers, A. F. Tumor dormancy and metastasis. Adv. Cancer Res. 102, 67–101 (2009).
  Article CAS PubMed Google Scholar
• Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195–198 (2008).
  Article CAS PubMed Google Scholar
• Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).
  Article CAS PubMed Google Scholar
• Moserle, L., Amadori, A. & Indraccolo, S. The angiogenic switch: implications in the regulation of tumor dormancy. Curr. Mol. Med. 9, 935–941 (2009).
  Article CAS PubMed Google Scholar
• Olaso, E. et al. Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology 37, 674–685 (2003).
  Article CAS PubMed Google Scholar
• Coenegrachts, L. et al. Anti-placental growth factor reduces bone metastasis by blocking tumor cell engraftment and osteoclast differentiation. Cancer Res. 70, 6537–6547 (2010).
  Article CAS PubMed Google Scholar
• Torry, R. J. et al. Hypoxia increases placenta growth factor expression in human myocardium and cultured neonatal rat cardiomyocytes. J. Heart Lung Transplant. 28, 183–190 (2009).
  Article PubMed PubMed Central Google Scholar
• Maegdefrau, U. et al. Bone morphogenetic protein 4 is induced in hepatocellular carcinoma by hypoxia and promotes tumour progression. J. Pathol. 218, 520–529 (2009).
  Article CAS PubMed Google Scholar
• Manisterski, M., Golan, M., Amir, S., Weisman, Y. & Mabjeesh, N. J. Hypoxia induces PTHrP gene transcription in human cancer cells through the HIF-2α. Cell Cycle 9, 3723–3729 (2010).
  Article CAS PubMed Google Scholar
• Moen, I. et al. Hyperoxic treatment induces mesenchymal-to-epithelial transition in a rat adenocarcinoma model. PLoS One 4, e6381 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, J. et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc. Natl Acad. Sci. USA 100, 7785–7790 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Mamluk, R. et al. Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. mAbs 2, 199–208 (2010).
  Article PubMed PubMed Central Google Scholar
• Bagri, A. et al. Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin. Cancer Res. 16, 3887–3900 (2010).
  Article CAS PubMed Google Scholar
• Whitehurst, B. et al. Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int. J. Cancer 121, 2181–2191 (2007).
  Article CAS PubMed Google Scholar
• Rowe, D. H. et al. Anti-VEGF antibody suppresses primary tumor growth and metastasis in an experimental model of Wilms' tumor. J. Pediatr. Surg. 35, 30–32 (2000).
  Article CAS PubMed Google Scholar
• Miles, D. et al. Disease course patterns following discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J. Clin. Oncol. 29, 83–88 (2011).
  Article CAS PubMed Google Scholar
• Valachis, A. et al. Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res. Treat. 122, 1–7 (2010).
  Article CAS PubMed Google Scholar
• Grothey, A. & Ellis, L. M. Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer J. 14, 170–177 (2008).
  Article CAS PubMed Google Scholar
• Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).
  Article CAS PubMed Google Scholar
• Reck, M. et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann. Oncol. 21, 1804–1809 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Escudier, B. et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J. Clin. Oncol. 28, 2144–2150 (2010).
  Article CAS PubMed Google Scholar
• Allegra, C. J. et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J. Clin. Oncol. 29, 11–16 (2011).
  Article CAS PubMed Google Scholar
• Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 116, 2610–2621 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• di Tomaso, E. et al. Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res. 71, 19–28 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Norden, A. D., Drappatz, J. & Wen, P. Y. Antiangiogenic therapies for high-grade glioma. Nat. Rev. Neurol. 5, 610–620 (2009).
  Article CAS PubMed Google Scholar
• Blouw, B. et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4, 133–146 (2003).
  Article CAS PubMed Google Scholar
• Kamoun, W. S. et al. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J. Clin. Oncol. 27, 2542–2552 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, R. et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833 (2010).
  Article CAS PubMed Google Scholar
• Soda, Y. et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc. Natl Acad. Sci. USA 108, 4274–4280 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
  Article CAS PubMed Google Scholar
• Nagy, J. A., Chang, S. H., Shih, S. C., Dvorak, A. M. & Dvorak, H. F. Heterogeneity of the tumor vasculature. Semin. Thromb. Hemost. 36, 321–331 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Koh, Y. J. et al. Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage. Cancer Cell 18, 171–184 (2010).
  Article CAS PubMed Google Scholar
• Gerhardt, H. & Semb, H. Pericytes: gatekeepers in tumour cell metastasis? J. Mol. Med. 86, 135–144 (2008).
  Article PubMed Google Scholar
• Skuli, N. et al. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood 114, 469–477 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, L. et al. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res. 69, 7905–7910 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Hiratsuka, S. et al. C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. Proc. Natl Acad. Sci. USA 108, 302–307 (2011).
  Article CAS PubMed Google Scholar
• Fischer, C., Mazzone, M., Jonckx, B. & Carmeliet, P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat. Rev. Cancer 8, 942–956 (2008).
  Article CAS PubMed Google Scholar
• Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).
  Article CAS PubMed Google Scholar
• Dimova, E. Y., Michiels, C. & Kietzmann, T. Kinases as upstream regulators of the HIF system: their emerging potential as anti-cancer drug targets. Curr. Pharm. Des. 15, 3867–3877 (2009).
  Article CAS PubMed Google Scholar
• Pietras, A., Johnsson, A. S. & Påhlman, S. The HIF-2alpha-driven pseudo-hypoxic phenotype in tumor aggressiveness, differentiation, and vascularization. Curr. Top. Microbiol. Immunol. 345, 1–20 (2010).
  CAS PubMed Google Scholar
• Qing, G. & Simon, M. C. Hypoxia inducible factor-2alpha: a critical mediator of aggressive tumor phenotypes. Curr. Opin. Genet. Dev. 19, 60–66 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Fraisl, P., Baes, M. & Carmeliet, P. Hungry for blood vessels: linking metabolism and angiogenesis. Dev. Cell 14, 313–314 (2008).
  Article CAS PubMed Google Scholar
• Jokilehto, T. & Jaakkola, P. M. The role of HIF prolyl hydroxylases in tumour growth. J. Cell. Mol. Med. 14, 758–770 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Quaegebeur, A. & Carmeliet, P. Oxygen sensing: a common crossroad in cancer and neurodegeneration. Curr. Top. Microbiol. Immunol. 345, 71–103 (2010).
  CAS PubMed Google Scholar
• Carmeliet, P. et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).
  Article CAS PubMed Google Scholar
• Wu, X. Z., Xie, G. R. & Chen, D. Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J. Gastroenterol. Hepatol. 22, 1178–1182 (2007).
  Article CAS PubMed Google Scholar
• Bedogni, B. et al. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell 8, 443–454 (2005).
  Article CAS PubMed Google Scholar
• Klein, T. J. & Glazer, P. M. The tumor microenvironment and DNA repair. Semin. Radiat. Oncol. 20, 282–287 (2010).
  Article PubMed PubMed Central Google Scholar
• Amberger-Murphy, V. Hypoxia helps glioma to fight therapy. Curr. Cancer Drug Targets 9, 381–390 (2009).
  Article CAS PubMed Google Scholar
• Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).
  Article CAS PubMed Google Scholar
• Heddleston, J. M. et al. Hypoxia inducible factors in cancer stem cells. Br. J. Cancer 102, 789–795 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mohyeldin, A., Garzón-Muvdi, T. & Quiñones-Hinojosa, A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7, 150–161 (2010).
  Article CAS PubMed Google Scholar
• Moeller, B. J. et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8, 99–110 (2005).
  Article CAS PubMed Google Scholar
• Lewis, C. E., De Palma, M. & Naldini, L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 67, 8429–8432 (2007).
  Article CAS PubMed Google Scholar
• Rosmorduc, O. & Housset, C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin. Liver Dis. 30, 258–270 (2010).
  Article CAS PubMed Google Scholar
• Bar, E. E. Glioblastoma, cancer stem cells and hypoxia. Brain Pathol. 21, 119–129 (2011).
  Article PubMed Google Scholar
• Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501–513 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).
  Article CAS PubMed Google Scholar
• Butler, J. M., Kobayashi, H. & Rafii, S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat. Rev. Cancer 10, 138–146 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gonzalez-Moreno, O. et al. VEGF elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop. Exp. Cell Res. 316, 554–567 (2010).
  Article CAS PubMed Google Scholar
• Hart, I. R. New evidence for tumour embolism as a mode of metastasis. J. Pathol. 219, 275–276 (2009).
  Article PubMed Google Scholar
• Zagzag, D. et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab. Invest. 86, 1221–1232 (2006).
  Article CAS PubMed Google Scholar
• Lee, Y. J. et al. Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer Res. 70, 8357–8367 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Rofstad, E. K. & Mathiesen, B. Metastasis in melanoma xenografts is associated with tumor microvascular density rather than extent of hypoxia. Neoplasia 12, 889–898 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Melnyk, O., Shuman, M. A. & Kim, K. J. Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth. Cancer Res. 56, 921–924 (1996).
  CAS PubMed Google Scholar
• Hotz, H. G. et al. Evaluation of vascular endothelial growth factor blockade and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer. J. Gastrointest. Surg. 7, 220–227 (2003).
  Article PubMed Google Scholar
• Bais, C. et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141, 166–177 (2010).
  Article CAS PubMed Google Scholar
• Melnyk, O., Zimmerman, M., Kim, K. J. & Shuman, M. Neutralizing anti-vascular endothelial growth factor antibody inhibits further growth of established prostate cancer and metastases in a pre-clinical model. J. Urol. 161, 960–963 (1999).
  Article CAS PubMed Google Scholar
• Kanai, T. et al. Anti-tumor and anti-metastatic effects of human-vascular-endothelial-growth-factor-neutralizing antibody on human colon and gastric carcinoma xenotransplanted orthotopically into nude mice. Int. J. Cancer 77, 933–936 (1998).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Verheul, H. M. et al. Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin. Cancer Res. 13, 4201–4208 (2007).
  Article CAS PubMed Google Scholar
• Zhang, W. et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin. Cancer Res. 16, 3420–3430 (2010).
  Article CAS PubMed Google Scholar
• Zhang, D. et al. Suppression of tumor growth and metastasis by simultaneously blocking vascular endothelial growth factor (VEGF)-A and VEGF-C with a receptor-immunoglobulin fusion protein. Cancer Res. 70, 2495–2503 (2010).
  Article CAS PubMed Google Scholar
• Matsui, J. et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin. Cancer Res. 14, 5459–5465 (2008).
  Article CAS PubMed Google Scholar
• Yang, H., Jager, M. J. & Grossniklaus, H. E. Bevacizumab suppression of establishment of micrometastases in experimental ocular melanoma. Invest. Ophthalmol. Vis. Sci. 51, 2835–2842 (2010).
  Article PubMed PubMed Central Google Scholar
• Mizobe, T. et al. Efficacy of the combined use of bevacizumab and irinotecan as a postoperative adjuvant chemotherapy in colon carcinoma. Oncol. Rep. 20, 517–523 (2008).
  CAS PubMed Google Scholar
• Osusky, K. L. et al. The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels. Angiogenesis 7, 225–233 (2004).
  Article CAS PubMed Google Scholar
• Imaizumi, T., Aoyagi, K., Miyagi, M. & Shirouzu, K. Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model. Surg. Today 40, 851–857 (2010).
  Article CAS PubMed Google Scholar
• Ninomiya, S. et al. Effect of bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, on peritoneal metastasis of MNK-45P human gastric cancer in mice. J. Surg. Res. 154, 196–202 (2009).
  Article CAS PubMed Google Scholar
• Warren, R. S., Yuan, H., Matli, M. R., Gillett, N. A. & Ferrara, N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J. Clin. Invest. 95, 1789–1797 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Asano, M., Yukita, A., Matsumoto, T., Kondo, S. & Suzuki, H. Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. Cancer Res. 55, 5296–5301 (1995).
  CAS PubMed Google Scholar
• Sweeney, P. et al. Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin. Cancer Res. 8, 2714–2724 (2002).
  CAS PubMed Google Scholar
• Zhang, L. et al. In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model. Neoplasia 11, 426–435 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Pignochino, Y. et al. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol. Cancer 8, 118 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Yin, J. J., Zhang, L., Munasinghe, J., Linnoila, R. I. & Kelly, K. Cediranib/AZD2171 inhibits bone and brain metastasis in a preclinical model of advanced prostate cancer. Cancer Res. 70, 8662–8673 (2010).
  Article CAS PubMed Google Scholar
• Shaheen, R. M. et al. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res. 59, 5412–5416 (1999).
  CAS PubMed Google Scholar
• Lang, S. A. et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol. Cancer Ther. 7, 3509–3518 (2008).
  Article CAS PubMed Google Scholar
• Hu, L. et al. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin. Cancer Res. 11, 6966–6971 (2005).
  Article CAS PubMed Google Scholar
• Amagai, Y. et al. Combination therapy of interleukin-2 and sorafenib improves survival benefits and prevents spontaneous pulmonary metastasis in murine renal cell carcinoma models. Jpn J. Clin. Oncol. 40, 503–507 (2010).
  Article PubMed Google Scholar
• Schomber, T. et al. Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol. Cancer Ther. 8, 55–63 (2009).
  Article CAS PubMed Google Scholar
• Rowe, D. H. et al. Suppression of primary tumor growth in a mouse model of human neuroblastoma. J. Pediatr. Surg. 35, 977–981 (2000).
  Article CAS PubMed Google Scholar
• Gandhi, L. et al. Sunitinib prolongs survival in genetically engineered mouse models of multistep lung carcinogenesis. Cancer Prev. Res. (Phila.) 2, 330–337 (2009).
  Article CAS Google Scholar