Advanced search
Publication Cover
Expert Review of Anticancer Therapy Volume 7, 2007 - Issue 4
Submit an article Journal homepage
59
Views
9
CrossRef citations to date
0
Altmetric
Review

Targeting the vascular endothelial growth factor pathway in the treatment of multiple myeloma

Klaus Podar Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, 44 Binney Street, Boston, MA 02115, USA. [email protected]
,
Paul G Richardson Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, 44 Binney Street, Boston, MA 02115, USA. [email protected]
,
Dharminder Chauhan Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, 44 Binney Street, Boston, MA 02115, USA. [email protected]
&
Kenneth C Anderson Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, 44 Binney Street, Boston, MA 02115, USA. [email protected]
Pages 551-566 | Published online: 10 Jan 2014

References

  • Cohen HJ, Crawford J, Rao MK, Pieper CF, Currie MS. Racial differences in the prevalence of monoclonal gammopathy in a community-based sample of the elderly. Am. J. Med.104, 439–444 (1998).
  • Malpas JS, Bergsagel DE, Kyle RA, Anderson KC. Multiple Myeloma: Biology and Management. Oxford University Press, Oxford, UK (1998).
  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science219, 983–985 (1983).
  • Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun.161, 851–858 (1989).
  • Connolly DT, Olander JV, Heuvelman D et al. Human vascular permeability factor. Isolation from U937 cells. J. Biol. Chem.264, 20017–20024 (1989).
  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science246, 1306–1309 (1989).
  • Keck PJ, Hauser SD, Krivi G et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science246, 1309–1312 (1989).
  • Olofsson B, Pajusola K, Kaipainen A et al. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Natl Acad. Sci. USA93, 2576–2581 (1996).
  • Joukov V, Pajusola K, Kaipainen A et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J.15, 1751 (1996).
  • Achen MG, Jeltsch M, Kukk E et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc. Natl Acad. Sci. USA95, 548–553 (1998).
  • Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl Acad. Sci. USA88, 9267–9271 (1991).
  • Maglione D, Guerriero V, Viglietto G et al. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene8, 925–931 (1993).
  • Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol.5, 1806–1814 (1991).
  • Tischer E, Mitchell R, Hartman T et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem.266, 11947–11954 (1991).
  • Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem.267, 26031–26037 (1992).
  • Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell.4, 1317–1326 (1993).
  • Keyt BA, Berleau LT, Nguyen HV et al. The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J. Biol. Chem.271, 7788–7795 (1996).
  • Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc. Natl Acad. Sci. USA94, 7192–7197 (1997).
  • Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic–helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA92, 5510–5514 (1995).
  • Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl Acad. Sci. USA93, 10595–10599 (1996).
  • Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature359, 843–845 (1992).
  • Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature359, 845–848 (1992).
  • Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J. Biol. Chem.271, 736–741 (1996).
  • Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr. Rev.18, 4–25 (1997).
  • Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J.13, 9–22 (1999).
  • Brauchle M, Funk JO, Kind P, Werner S. Ultraviolet B and H2O2 are potent inducers of vascular endothelial growth factor expression in cultured keratinocytes. J. Biol. Chem.271, 21793–21797 (1996).
  • Kieser A, Weich HA, Brandner G, Marme D, Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene9, 963–969 (1994).
  • Rak J, Mitsuhashi Y, Bayko L et al. Mutant RAS oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res.55, 4575–4580 (1995).
  • Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D. Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J. Biol. Chem.270, 25915–25919 (1995).
  • Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer2, 727–739 (2002).
  • D’Arcangelo D, Facchiano F, Barlucchi LM et al. Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression. Circ. Res.86, 312–318 (2000).
  • He C, Chen X. Transcription regulation of the VEGF gene by the BMP/Smad pathway in the angioblast of zebrafish embryos. Biochem. Biophys. Res. Commun.329, 324–330 (2005).
  • Gering M, Patient R. Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos. Dev. Cell8, 389–400 (2005).
  • Podar K, Anderson KC. The pathophysiological role of VEGF in hematological malignancies: therapeutic implications. Blood105, 1383–1395 (2005).
  • Fiedler W, Graeven U, Ergun S et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood89, 1870–1875 (1997).
  • Aguayo A, Kantarjian H, Manshouri T et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood96, 2240–2245 (2000).
  • Chen H, Treweeke AT, West DC et al.In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood96, 3181–3187 (2000).
  • Dias S, Hattori K, Zhu Z et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J. Clin. Invest.106, 511–521 (2000).
  • Krauth MT, Simonitsch I, Aichberger KJ et al. Immunohistochemical detection of VEGF in the bone marrow of patients with chronic myeloid leukemia and correlation with the phase of disease. Am. J. Clin. Pathol.121, 473–481 (2004).
  • Ghannadan M, Wimazal F, Simonitsch I et al. Immunohistochemical detection of VEGF in the bone marrow of patients with acute myeloid leukemia. Correlation between VEGF expression and the FAB category. Am. J. Clin. Pathol.119, 663–671 (2003).
  • Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res.59, 728–733 (1999).
  • Bellamy WT. Expression of vascular endothelial growth factor and its receptors in multiple myeloma and other hematopoietic malignancies. Semin. Oncol.28, 551–559 (2001).
  • Satoh H, Yoshida MC, Matsushime H, Shibuya M, Sasaki M. Regional localization of the human c-ros-1 on 6q22 and flt on 13q12. Jpn. J. Cancer Res.78, 772–775 (1987).
  • de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science255, 989–991 (1992).
  • Shibuya M, Yamaguchi S, Yamane A et al. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene5, 519–524 (1990).
  • Terman BI, Dougher-Vermazen M, Carrion ME et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun.187, 1579–1586 (1992).
  • Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc. Natl Acad. Sci. USA90, 7533–7537 (1993).
  • Sait SN, Dougher-Vermazen M, Shows TB, Terman BI. The kinase insert domain receptor gene (KDR) has been relocated to chromosome 4q11 – >q12. Cytogenet. Cell Genet.70, 145–146 (1995).
  • Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature376, 66–70 (1995).
  • Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature376, 62–66 (1995).
  • Gerber HP, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J. Biol. Chem.272, 23659–23667 (1997).
  • Keyt BA, Nguyen HV, Berleau LT et al. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J. Biol. Chem.271, 5638–5646 (1996).
  • Millauer B, Wizigmann-Voos S, Schnurch H et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell72, 835–846 (1993).
  • Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood87, 3336–3343 (1996).
  • Clauss M, Weich H, Breier G et al. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem.271, 17629–17634 (1996).
  • Charnock-Jones DS, Sharkey AM, Boocock CA et al. Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol. Reprod.51, 524–530 (1994).
  • Takahashi T, Shirasawa T, Miyake K et al. Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: Flt-1 and VEGF expression in renal mesangial cells. Biochem. Biophys. Res. Commun.209, 218–226 (1995).
  • Grosskreutz CL, Anand-Apte B, Duplaa C et al. Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc. Res.58, 128–136 (1999).
  • Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N. Engl. J. Med.337, 1584–1590 (1997).
  • Peichev M, Naiyer AJ, Pereira D et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood95, 952–958 (2000).
  • Gill M, Dias S, Hattori K et al. Vascular trauma induces rapid but transient mobilization of VEGFR2+AC133+ endothelial precursor cells. Circ. Res.88, 167–174 (2001).
  • Oberg C, Waltenberger J, Claesson-Welsh L, Welsh M. Expression of protein tyrosine kinases in islet cells: possible role of the Flk-1 receptor for β-cell maturation from duct cells. Growth Factors10, 115–126 (1994).
  • Yang K, Cepko CL. Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J. Neurosci.16, 6089–6099 (1996).
  • Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res.55, 5687–5692 (1995).
  • Ergun S, Kilic N, Fiedler W, Mukhopadhyay AK. Vascular endothelial growth factor and its receptors in normal human testicular tissue. Mol. Cell. Endocrinol.131, 9–20 (1997).
  • Fong GH, Zhang L, Bryce DM, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development126, 3015–3025 (1999).
  • Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci. STKE2001(112), RE21 (2001).
  • Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA95, 9349–9354 (1998).
  • Hattori K, Heissig B, Wu Y et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nat. Med.8, 841–849 (2002).
  • Gerber HP, Malik AK, Solar GP et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature417, 954–958 (2002).
  • Sawano A, Iwai S, Sakurai Y et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood97, 785–791 (2001).
  • Luttun A, Tjwa M, Carmeliet P. Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann. NY Acad. Sci.979, 80–93 (2002).
  • LeCouter J, Moritz DR, Li B et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science299, 890–893 (2003).
  • Hiratsuka S, Nakamura K, Iwai S et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell2, 289–300 (2002).
  • Yaccoby S, Barlogie B, Epstein J. Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations. Blood92, 2908–2913 (1998).
  • Breier G, Albrecht U, Sterrer S, Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development114, 521–532 (1992).
  • Jakeman LB, Winer J, Bennett GL, Altar CA, Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J. Clin. Invest.89, 244–253 (1992).
  • Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med.285, 1182–1186 (1971).
  • Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature407, 249–257 (2000).
  • Brien SE, Zagzag D, Brem S. Rapid in situ cellular kinetics of intracerebral tumor angiogenesis using a monoclonal antibody to bromodeoxyuridine. Neurosurgery25, 715–719 (1989).
  • Liotta LA, Kohn EC. The microenvironment of the tumour–host interface. Nature411, 375–379 (2001).
  • Gagne P, Akalu A, Brooks PC. Challenges facing antiangiogenic therapy for cancer: impact of the tumor extracellular environment. Expert Rev. Anticancer Ther.4, 129–140 (2004).
  • Ribatti D, Nico B, Vacca A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene25, 4257–4266 (2006).
  • Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer3, 401–410 (2003).
  • Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinical implications. J. Clin. Oncol.18, 1135–1149 (2000).
  • Nangia-Makker P, Honjo Y, Sarvis R et al. Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am. J. Pathol.156, 899–909 (2000).
  • Gamble J, Meyer G, Noack L et al. B1 integrin activation inhibits in vitro tube formation: effects on cell migration, vacuole coalescence and lumen formation. Endothelium7, 23–34 (1999).
  • Yang S, Graham J, Kahn JW, Schwartz EA, Gerritsen ME. Functional roles for PECAM-1 (CD31) and VE-cadherin (CD144) in tube assembly and lumen formation in three-dimensional collagen gels. Am. J. Pathol.155, 887–895 (1999).
  • Holash J, Maisonpierre PC, Compton D et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science284, 1994–1998 (1999).
  • Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat. Rev. Cancer2, 826–835 (2002).
  • Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am. J. Pathol.156, 361–381 (2000).
  • Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl Acad. Sci. USA97, 14608–14613 (2000).
  • Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature407, 242–248 (2000).
  • Hendrix MJ, Seftor EA, Meltzer PS et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc. Natl Acad. Sci. USA98, 8018–8023 (2001).
  • Folkman J. Can mosaic tumor vessels facilitate molecular diagnosis of cancer? Proc. Natl Acad. Sci. USA98, 398–400 (2001).
  • Rafii S. Circulating endothelial precursors: mystery, reality, and promise. J. Clin. Invest.105, 17–19 (2000).
  • Lyden D, Hattori K, Dias S et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med.7, 1194–1201 (2001).
  • Luttun A, Tjwa M, Moons L et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med.8, 831–840 (2002).
  • Vacca A, Ribatti D, Roncali L et al. Bone marrow angiogenesis and progression in multiple myeloma. Br. J. Haematol.87, 503–508 (1994).
  • Vacca A, Ribatti D, Presta M et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood93, 3064–3073 (1999).
  • Ribatti D, Vacca A, Nico B et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br. J. Cancer79, 451–455 (1999).
  • Munshi N, Wilson CS, Penn J. Angiogenesis in newly diagnosed multiple myeloma: poor prognosis with increased microvessel density (MVD) in bone marrow biopsies. Blood92(Suppl.), A98 (1998).
  • Schreiber S, Ackermann J, Obermair A et al. Multiple myeloma with deletion of chromosome 13q is characterized by increased bone marrow neovascularization. Br. J. Haematol.110, 605–609 (2000).
  • Sezer O, Niemoller K, Eucker J et al. Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann. Hematol.79, 574–577 (2000).
  • Rajkumar SV, Leong T, Roche PC et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin. Cancer Res.6, 3111–3116 (2000).
  • Kyle RA, Rajkumar SV. Multiple myeloma. N. Engl. J. Med.351, 1860–1873 (2004).
  • Asosingh K, De Raeve H, Menu E et al. Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity. Blood103, 3131–3137 (2004).
  • Kumar S, Rajkumar SV, Kimlinger T, Greipp PR, Witzig TE. CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations. Leukemia19, 1466–1470 (2005).
  • Kumar S, Fonseca R, Dispenzieri A et al. Prognostic value of angiogenesis in solitary bone plasmacytoma. Blood101, 1715–1717 (2003).
  • Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am. J. Pathol.133, 95–109 (1988).
  • Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol.160, 985–1000 (2002).
  • Baish JW, Jain RK. Fractals and cancer. Cancer Res.60, 3683–3688 (2000).
  • Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med.3, 177–182 (1997).
  • Ruoslahti E. Specialization of tumour vasculature. Nat. Rev. Cancer2, 83–90 (2002).
  • St Croix B, Rago C, Velculescu V et al. Genes expressed in human tumor endothelium. Science289, 1197–1202 (2000).
  • Vacca A, Ria R, Semeraro F et al. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood102, 3340–3348 (2003).
  • Streubel B, Chott A, Huber D et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N. Engl. J. Med.351, 250–259 (2004).
  • Streubel B, Drach J, Huber D et al. Bone marrow microvessel endothelial cells in multiple myeloma harbor myeloma- associated chromosomal translocations. Haematologica90, 54 (2005).
  • Tavassoli M. Structure and function of sinusoidal endothelium of bone marrow. Prog. Clin. Biol. Res.59B, 249–256 (1981).
  • Rafii S, Mohle R, Shapiro F, Frey BM, Moore MA. Regulation of hematopoiesis by microvascular endothelium. Leuk. Lymphoma27, 375–386 (1997).
  • Rafii S, Shapiro F, Rimarachin J et al. Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion. Blood84, 10–19 (1994).
  • Mohle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA94, 663–668 (1997).
  • Avecilla ST, Hattori K, Heissig B et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat. Med.10, 64–71 (2004).
  • Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development125, 725–732 (1998).
  • Nishikawa SI. A complex linkage in the developmental pathway of endothelial and hematopoietic cells. Curr. Opin. Cell Biol.13, 673–678 (2001).
  • Carmeliet P, Ferreira V, Breier G et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature380, 435–439 (1996).
  • Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature380, 439–442 (1996).
  • Cerdan C, Rouleau A, Bhatia M. VEGF-A165 augments erythropoietic development from human embryonic stem cells. Blood103, 2504–2512 (2004).
  • Bruckner K, Kockel L, Duchek P, Luque CM, Rorth P, Perrimon N. The PDGF/VEGF receptor controls blood cell survival in Drosophila. Dev. Cell7, 73–84 (2004).
  • Gabrilovich DI, Chen HL, Girgis KR et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med.2, 1096–1103 (1996).
  • Nakagawa M, Kaneda T, Arakawa T et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett.473, 161–164 (2000).
  • Henriksen K, Karsdal M, Delaisse JM, Engsig MT. RANKL and vascular endothelial growth factor (VEGF) induce osteoclast chemotaxis through an ERK1/2-dependent mechanism. J. Biol. Chem.278, 48745–48753 (2003).
  • Midy V, Plouet J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem. Biophys. Res. Commun.199, 380–386 (1994).
  • Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med.2, 992–997 (1996).
  • Compernolle V, Brusselmans K, Acker T et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat. Med.8, 702–710 (2002).
  • Oosthuyse B, Moons L, Storkebaum E et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat. Genet.28, 131–138 (2001).
  • Ria R, Roccaro AM, Merchionne F, Vacca A, Dammacco F, Ribatti D. Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia17, 1961–1966 (2003).
  • Podar K, Tai YT, Davies FE et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood98, 428–435 (2001).
  • Vincent L, Jin DK, Karajannis MA et al. Fetal stromal-dependent paracrine and intracrine vascular endothelial growth factor-a/vascular endothelial growth factor receptor-1 signaling promotes proliferation and motility of human primary myeloma cells. Cancer Res.65, 3185–3192 (2005).
  • Sweeney CJ, Miller KD, Sissons SE et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res.61, 3369–3372 (2001).
  • Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Natl Acad. Sci. USA99, 4349–4354 (2002).
  • Podar K, Tai YT, Lin BK et al. Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with β 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC α activation. J. Biol. Chem.277, 7875–7881 (2002).
  • Podar K, Shringarpure R, Tai YT et al. Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib. Cancer Res.64, 7500–7506 (2004).
  • Le Gouill S, Podar K, Amiot M et al. VEGF induces MCL-1 upregulation and protects multiple myeloma cells against apoptosis. Blood104(9), 2886–2892 (2004).
  • Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov.3, 391–400 (2004).
  • Willett CG, Boucher Y, di Tomaso E et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med.10, 145–147 (2004).
  • Wood JM, Bold G, Buchdunger E et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res.60, 2178–2189 (2000).
  • Thomas AL, Morgan B, Drevs J et al. Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin. Oncol.30, 32–38 (2003).
  • Lin B, Podar K, Gupta D et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res.62, 5019–5026 (2002).
  • Kumar R, Knick VB, Rudolph SK et al. GW786034: a pan-inhibitor of VEGF receptors with potent anti-tumor and anti-angiogenic activity. AACR–NCI–EORTC International Conference: Molecular Targets and Cancer Therapeutics58–59 (2005).
  • GlaxoSmithKline. Pazopanib hydrochloride. Pharmacopeial Forum32, 217 (2006).
  • Hurwitz H, Dowlati A, Savage S et al. Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors. J. Clin. Oncol.23, 3012 (2005).
  • Podar K, Tonon G, Sattler M et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc. Natl Acad. Sci. USA103(51), 19478–19483 (2006).
  • Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res.60, 6253–6258 (2000).
  • Holash J, Davis S, Papadopoulos N et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc. Natl Acad. Sci. USA99, 11393–11398 (2002).
  • Kim ES, Serur A, Huang J et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc. Natl Acad. Sci. USA99, 11399–11404 (2002).
  • O’Farrell AM, Yuen HA, Smolich Bet al. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk. Res.7, 679–689 (2004).
  • Giles FJ, Stopeck AT, Silverman LRet al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood102(3), 795–801 (2003).
  • Fiedler W, Mesters R, Tinnefeld Het al. A Phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood102(8), 2763–2767 (2003).
  • O’Farrell AM, Abrams TJ, Yuen HA et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood101, 3597–3605 (2003).
  • Beebe JS, Jani JP, Knauth E et al. Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res.63, 7301–7309 (2003).
  • Bates D. ZD-6474. AstraZeneca. Curr. Opin. Investig. Drugs4, 1468–1472 (2003).
  • Lowinger TB, Riedl B, Dumas J, Smith RA. Design and discovery of small molecules targeting raf-1 kinase. Curr. Pharm. Des.8, 2269–2278 (2002).
  • Richly H, Kupsch P, Passage K et al. A Phase I clinical and pharmacokinetic study of the Raf kinase inhibitor (RKI) BAY 43–9006 administered in combination with doxorubicin in patients with solid tumors. Int. J. Clin. Pharmacol. Ther.41, 620–621 (2003).
  • D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl Acad. Sci. USA91, 4082–4085 (1994).
  • Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med.341, 1565–1571 (1999).
  • Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer4, 314–322 (2004).
  • Hideshima T, Chauhan D, Shima Y et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood96, 2943–2950 (2000).
  • D’Amato RJ, Lentzsch S, Anderson KC, Rogers MS. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin. Oncol.28, 597–601 (2001).
  • Yabu T, Tomimoto H, Taguchi Y, Yamaoka S, Igarashi Y, Okazaki T. Thalidomide-induced anti-angiogenic action is mediated by ceramide through depletion of VEGF receptors, and antagonized by sphingosine-1-phosphate. Blood106(1), 125–134 (2005).
  • Davies FE, Raje N, Hideshima T et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood98, 210–216 (2001).
  • Richardson PG, Schlossman RL, Weller E et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood100, 3063–3067 (2002).
  • Schey SA, Fields P, Bartlett JB et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol.22, 3269–3276 (2004).
  • Cushman M, He HM, Katzenellenbogen JA, Lin CM, Hamel E. Synthesis, antitubulin and antimitotic activity, and cytotoxicity of analogs of 2-methoxyestradiol, an endogenous mammalian metabolite of estradiol that inhibits tubulin polymerization by binding to the colchicine binding site. J. Med. Chem.38, 2041–2049 (1995).
  • Klauber N, Parangi S, Flynn E, Hamel E, D’Amato RJ. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res.57, 81–86 (1997).
  • Lottering ML, Haag M, Seegers JC. Effects of 17 β-estradiol metabolites on cell cycle events in MCF-7 cells. Cancer Res.52, 5926–5932 (1992).
  • Mukhopadhyay T, Roth JA. Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene14, 379–384 (1997).
  • Schumacher G, Neuhaus P. The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors. J. Cancer Res. Clin. Oncol.127, 405–410 (2001).
  • Kumar AP, Garcia GE, Slaga TJ. 2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells. Mol. Carcinog.31, 111–124 (2001).
  • Chauhan D, Catley L, Hideshima T et al. 2-methoxyestradiol overcomes drug resistance in multiple myeloma cells. Blood100, 2187–2194 (2002).
  • Graff JR, McNulty AM, Hanna KR et al. The protein kinase Cβ-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res.65, 7462–7469 (2005).
  • Keyes K, Cox K, Treadway P et al. An in vitro tumor model: analysis of angiogenic factor expression after chemotherapy. Cancer Res.62, 5597–5602 (2002).
  • Keyes KA, Mann L, Sherman M et al. LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother. Pharmacol.53, 133–140 (2004).
  • Herbst RS. Targeted therapy using novel agents in the treatment of non-small-cell lung cancer. Clin. Lung Cancer.3(Suppl. 1), S30–S38 (2002).
  • Podar K, Raab MS, Zhang J et al. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor Enzastaurin (LY317615.HCl). Blood109(4), 1669–1677 (2006).
  • MacDonald TJ, Taga T, Shimada H et al. Preferential susceptibility of brain tumors to the antiangiogenic effects of an α(v) integrin antagonist. Neurosurgery48, 151–157 (2001).
  • Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL. Cilengitide targeting of α(v)β(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res.62, 4263–4272 (2002).
  • Raguse JD, Gath HJ, Bier J, Riess H, Oettle H. Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. Oral Oncol.40, 228–230 (2004).
  • Nisato RE, Tille JC, Jonczyk A, Goodman SL, Pepper MS. αv β 3 and αv β 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis6, 105–119 (2003).
  • Moolenaar WH, Kranenburg O, Postma FR, Zondag GC. Lysophosphatidic acid: G-protein signalling and cellular responses. Curr. Opin. Cell Biol.9, 168–173 (1997).
  • Hu YL, Tee MK, Goetzl EJ et al. Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J. Natl Cancer Inst.93, 762–768 (2001).
  • Hideshima T, Chauhan D, Hayashi T et al. Antitumor activity of lysophosphatidic acid acyltransferase-β inhibitors, a novel class of agents, in multiple myeloma. Cancer Res.63, 8428–8436 (2003).
  • Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist8, 508–513 (2003).
  • Hideshima T, Richardson P, Chauhan D et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res.61, 3071–3076 (2001).
  • Hideshima T, Mitsiades C, Akiyama M et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood101, 1530–1534 (2003).
  • Hideshima T, Chauhan D, Hayashi T et al. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene22, 8386–8393 (2003).
  • Nawrocki ST, Bruns CJ, Harbison MT et al. Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol. Cancer Ther.1, 1243–1253 (2002).
  • Oikawa T, Sasaki T, Nakamura M et al. The proteasome is involved in angiogenesis. Biochem. Biophys. Res. Commun.246, 243–248 (1998).
  • LeBlanc R, Catley LP, Hideshima T et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res.62, 4996–5000 (2002).
  • Tai YT, Podar K, Gupta D et al. CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. Blood99, 1419–1427 (2002).
  • Tai YT, Catley LP, Mitsiades CS et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res.64, 2846–2852 (2004).
  • Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med.7, 987–989 (2001).
  • Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J. Clin. Invest.105, 1045–1047 (2000).
  • Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer4, 423–436 (2004).
  • Browder T, Butterfield CE, Kraling BM et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res.60, 1878–1886 (2000).
  • Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncol.2, 733–740 (2001).
  • Kamen BA, Rubin E, Aisner J, Glatstein E. High-time chemotherapy or high time for low dose. J. Clin. Oncol.18, 2935–2937 (2000).
  • Kerbel RS, Klement G, Pritchard KI, Kamen B. Continuous low-dose anti-angiogenic/metronomic chemotherapy: from the research laboratory into the oncology clinic. Ann. Oncol.13, 12–15 (2002).
  • Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR. Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma. Leukemia13, 469–472 (1999).
  • Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J. Natl Cancer Inst.94, 883–893 (2002).
  • Bertolini F, Mingrone W, Alietti A et al. Thalidomide in multiple myeloma, myelodysplastic syndromes and histiocytosis. Analysis of clinical results and of surrogate angiogenesis markers. Ann. Oncol.12, 987–990 (2001).
  • Moehler TM, Hawighorst H, Neben K et al. Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging. Int. J. Cancer93, 862–868 (2001).
  • Baur A, Bartl R, Pellengahr C, Baltin V, Reiser M. Neovascularization of bone marrow in patients with diffuse multiple myeloma: a correlative study of magnetic resonance imaging and histopathologic findings. Cancer101, 2599–2604 (2004).
  • Shaked Y, Bertolini F, Man S et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell7, 101–111 (2005).

Websites

  • National Cancer Institute: recent developments www.cancer.gov/clinicaltrials/developments
  • Clinical Trials www.clinicaltrials.gov

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.