Therapy-Induced Acute Recruitment of Circulating Endothelial Progenitor Cells to Tumors

The contribution of bone marrow–derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobilization of CEPs, which home to the viable tumor rim that characteristically remains after such therapy. Disruption of this CEP spike by antiangiogenic drugs or by genetic manipulation resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity. These findings also provide a mechanistic rationale for the enhanced efficacy of VDAs when combined with antiangiogenic drugs.

[1]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[2]  D. Hicklin,et al.  Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. , 1999, Cancer research.

[3]  W. Gerald,et al.  Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts , 1999, Nature.

[4]  S. Rafii,et al.  Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth , 2001, Nature Medicine.

[5]  E. Chérin,et al.  A new ultrasound instrument for in vivo microimaging of mice. , 2002, Ultrasound in medicine & biology.

[6]  Koichi Hattori,et al.  Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? , 2002, Nature Reviews Cancer.

[7]  R. Kerbel,et al.  Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. , 2003, Cancer research.

[8]  W. Gerald,et al.  Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. , 2003, Cancer cell.

[9]  W. Schaper,et al.  A different outlook on the role of bone marrow stem cells in vascular growth: bone marrow delivers software not hardware. , 2004, Circulation research.

[10]  M. Horsman,et al.  Vascular‐targeting therapies for treatment of malignant disease , 2004, Cancer.

[11]  S. Dimmeler,et al.  Endothelial Progenitor Cells: Characterization and Role in Vascular Biology , 2004, Circulation research.

[12]  R. Kerbel,et al.  Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. , 2005, Cancer research.

[13]  R. D'Amato,et al.  Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. , 2005, Cancer cell.

[14]  Luigi Naldini,et al.  Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. , 2005, Cancer cell.

[15]  Chryso Kanthou,et al.  Disrupting tumour blood vessels , 2005, Nature Reviews Cancer.

[16]  A. Rojiani,et al.  The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors. , 2005, International journal of radiation oncology, biology, physics.

[17]  B. Peters,et al.  Contribution of bone marrow–derived endothelial cells to human tumor vasculature , 2005, Nature Medicine.

[18]  Rinat Abramovitch,et al.  VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells , 2006, Cell.

[19]  Limor Chen,et al.  Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. , 2006, Cancer research.