Cross-talk between leukemic and endothelial cells promotes angiogenesis by VEGF activation of the Notch/Dll4 pathway.

Angiogenesis is suggested to be important for leukemogenesis and chemosensitivity in acute myeloid leukemia (AML). The vascular endothelial growth factor (VEGF) and Notch/Dll4 pathways have been identified as critical in the regulation of embryonic vascular development and tumor angiogenesis. However, the potential role of the Notch/Dll4 pathway in leukemia-endothelium cross-talk and its functional link with VEGF remains obscure. This study assessed the expression of VEGF and Notch/Dll4 pathway molecules in primary AML and investigated their biological function in the coculture of endothelial cells with AML cells. The results demonstrated that bone marrow vascularity in the newly diagnosed AML patients was increased and correlated with high VEGF and Dll4 expression. Patients with untreated AML expressed higher levels of VEGFR2, Notch1, Dll4 and Hes1 than healthy controls. Moreover, the activation of the Notch/Dll4 pathway is associated with poor prognosis in AML. In addition, AML cells were shown to increase endothelial cell proliferation in Transwell coculture. This was associated with concomitant activation of the Notch/Dll4 pathway and upregulation of its downstream genes, such as matrix metalloproteinases, resulting in the enhancement of endothelial cell migration and tube formation. Our study also showed that upregulation of Dll4 expression in AML cells by cDNA transfection suppressed VEGF-induced endothelial cell proliferation and angiogenesis in direct contact coculture. These results elucidate a novel mechanism by which the interplay between AML and endothelial cells promotes angiogenesis through the Notch/Dll4 pathway. Modulation of this pathway may, therefore, hold promise as a novel antiangiogenic strategy for the treatment of AML.

[1]  R. D'Amato,et al.  VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients , 2012, Angiogenesis.

[2]  A. Lluch,et al.  The single-nucleotide polymorphisms +936 C/T VEGF and −710 C/T VEGFR1 are associated with breast cancer protection in a Spanish population , 2012, Breast Cancer Research and Treatment.

[3]  C. Cogle,et al.  Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies , 2011, Journal of oncology.

[4]  Ø. Bruserud,et al.  Serum levels of endothelium-derived endocan are increased in patients with untreated acute myeloid leukemia , 2011, Hematology.

[5]  F. Gu,et al.  Notch1 is involved in migration and invasion of human breast cancer cells. , 2011, Oncology reports.

[6]  V. Yang,et al.  Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice. , 2011, Gastroenterology.

[7]  A. Harris,et al.  DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. , 2011, Cancer research.

[8]  Sarah J L Payne,et al.  Influence of the tumor microenvironment on angiogenesis. , 2011, Future oncology.

[9]  A. Capobianco,et al.  Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia. , 2011, Blood.

[10]  Y. Funahashi,et al.  Notch modulates VEGF action in endothelial cells by inducing Matrix Metalloprotease activity , 2011, Vascular cell.

[11]  B. Teicher.  Antiangiogenic agents and targets: A perspective. , 2011, Biochemical pharmacology.

[12]  A. Ikinciogullari,et al.  DOES SERUM SOLUBLE VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS HAVE DIFFERENT IMPORTANCE IN PEDIATRIC ACUTE LEUKEMIA AND MALIGNANT LYMPHOMA PATIENTS? , 2010, Pediatric hematology and oncology.

[13]  E. Scott,et al.  Leukemia regression by vascular disruption and antiangiogenic therapy. , 2010, Blood.

[14]  A. Palazzo,et al.  Past, present and future of targeted therapy in solid tumors. , 2010, Current cancer drug targets.

[15]  R. Marasca,et al.  Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia-derived Ang2 and VEGF. , 2010, Leukemia research.

[16]  Ø. Bruserud,et al.  Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and pharmacological modulation , 2010, European journal of haematology.

[17]  Hua Han,et al.  Notch signaling maintains proliferation and survival of the HL60 human promyelocytic leukemia cell line and promotes the phosphorylation of the Rb protein , 2010, Molecular and Cellular Biochemistry.

[18]  L. Fu,et al.  Transition of cleaved Notch1 and gene expression changes in myeloblastic leukemia cells stimulated with notch ligands. , 2009, Anticancer research.

[19]  Holger Gerhardt,et al.  Angiogenesis: a team effort coordinated by notch. , 2009, Developmental cell.

[20]  B. Wegiel,et al.  The role of VEGF and a functional link between VEGF and p27Kip1 in acute myeloid leukemia , 2009, Leukemia.

[21]  Ø. Bruserud,et al.  Primary human acute myeloid leukaemia cells increase the proliferation of microvascular endothelial cells through the release of soluble mediators , 2009, British journal of haematology.

[22]  A. Harris,et al.  Crosstalk of VEGF and Notch pathways in tumour angiogenesis: therapeutic implications. , 2009, Frontiers in bioscience.

[23]  R. Kalluri,et al.  Contribution of bone microenvironment to leukemogenesis and leukemia progression , 2009, Leukemia.

[24]  G. Thurston,et al.  VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis , 2008, British Journal of Cancer.

[25]  A. Ganser,et al.  Angiopoietin-2 predicts disease-free survival after allogeneic stem cell transplantation in patients with high-risk myeloid malignancies. , 2008, Blood.

[26]  M. Yao,et al.  Expression of angiopoietins and vascular endothelial growth factors and their clinical significance in acute myeloid leukemia. , 2008, Leukemia research.

[27]  Arndt F. Siekmann,et al.  Modulation of VEGF signalling output by the Notch pathway , 2008, BioEssays : news and reviews in molecular, cellular and developmental biology.

[28]  Adrian L Harris,et al.  Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. , 2008, Microvascular research.

[29]  Jin-Hwang Liu,et al.  Down-regulation of Notch-1 expression decreases PU.1-mediated myeloid differentiation signaling in acute myeloid leukemia. , 1992, International journal of oncology.

[30]  Wen Shi,et al.  Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. , 2007, Cancer research.

[31]  Weidong Jiang,et al.  Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. , 2007, Blood.

[32]  G. Thurston,et al.  Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting , 2007, Proceedings of the National Academy of Sciences.

[33]  Antonio Duarte,et al.  The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching , 2007, Proceedings of the National Academy of Sciences.

[34]  Minhong Yan,et al.  Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis , 2006, Nature.

[35]  Gavin Thurston,et al.  Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis , 2006, Nature.

[36]  Alfonso Martinez Arias,et al.  Notch, a Universal Arbiter of Cell Fate Decisions , 2006, Science.

[37]  Ø. Bruserud,et al.  Microvascular endothelial cells increase proliferation and inhibit apoptosis of native human acute myelogenous leukemia blasts , 2006, International journal of cancer.

[38]  A. Villemain,et al.  The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. , 2006, Cancer research.

[39]  A. Harris,et al.  Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer , 2006, Clinical Cancer Research.

[40]  M. Holderfield,et al.  HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes. , 2006, Biochemical and biophysical research communications.

[41]  Zhiwei Wang,et al.  Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. , 2006, Cancer research.

[42]  A. Harris,et al.  Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. , 2006, Blood.

[43]  K. Do,et al.  Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia. , 2005, Blood.

[44]  Adrian L Harris,et al.  Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. , 2005, Cancer research.

[45]  A. Harris,et al.  Notch signaling from tumor cells: a new mechanism of angiogenesis. , 2005, Cancer cell.

[46]  Gavin Thurston,et al.  Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Bongrand,et al.  Endothelial cell culture: protocol to obtain and cultivate human umbilical endothelial cells. , 2001, Journal of immunological methods.

[48]  W. Berdel,et al.  Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. , 2000, Blood.

[49]  G. Rodgers,et al.  Evidence of increased angiogenesis in patients with acute myeloid leukemia. , 2000, Blood.