Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?

Summary The growth and metastasis of the majority of tumours depends on the formation of new blood vessels. Angiogenic factors that are released by tumour cells promote activation, proliferation and migration of endothelial cells to the tumour tissue, allowing for rapid formation of functional neo-vessels. Endothelial cells contribute to tumour angiogenesis, and can originate from sprouting or co-option of neighbouring pre-existing vessels. Emerging evidence indicates that bone-marrow-derived circulating endothelial progenitor cells (CEPs) can contribute to the angiogenesis and growth of certain tumours. The introduction of wild-type bone marrow CEPs, which express the VEGF receptor (VEGFR)-2, restores tumour angiogenesis and growth in tumour-resistant mice, indicating that bone-marrow-derived cells are essential for the angiogenesis and growth of certain tumours. Co-mobilization of VEGFR1+ haematopoietic stem and progenitor cells facilitate the incorporation of CEPs into functional tumour neo-vessels. Mobilization of CEPs and pro-angiogenic haematopoietic cells from bone marrow is a dynamic process that requires angiogenic-factor-mediated activation of metalloproteinases (MMPs), specifically MMP-9, which lead to the release of soluble KIT ligand (sKitL). sKitL promotes the proliferation and motility of CEPs and haematopoietic cells within the bone-marrow microenvironment, thereby laying the framework for their mobilization to the peripheral circulation. Inhibition of either VEGFR1 or VEGFR2 signalling can only partially block tumour angiogenesis and growth. Conversely, simultaneous inhibition of VEGFR1 and VEGFR2 signalling results in impaired mobilization and recruitment of VEGFR1+ haematopoietic cells and VEGFR2+ CEPs to the tumour vasculature, and is highly effective in retarding the growth of certain tumours. Characterization and quantification of VEGFR2+CEPs and VEGFR1+ haematopoietic cells in the peripheral blood, and plasma levels of VEGF, sKitL, MMP-9 and placental growth factor might lead to their use as surrogate markers for assessing the response to therapy or progression of certain malignancies. Moreover, factors that are involved in the mobilization and incorporation of CEPs and pro-angiogenic haematopoietic cells provide new targets to block tumour angiogenesis and growth. The growth and metastasis of the majority of tumours depends on the formation of new blood vessels. Angiogenic factors that are released by tumour cells promote activation, proliferation and migration of endothelial cells to the tumour tissue, allowing for rapid formation of functional neo-vessels. Endothelial cells contribute to tumour angiogenesis, and can originate from sprouting or co-option of neighbouring pre-existing vessels. Emerging evidence indicates that bone-marrow-derived circulating endothelial progenitor cells (CEPs) can contribute to the angiogenesis and growth of certain tumours. The introduction of wild-type bone marrow CEPs, which express the VEGF receptor (VEGFR)-2, restores tumour angiogenesis and growth in tumour-resistant mice, indicating that bone-marrow-derived cells are essential for the angiogenesis and growth of certain tumours. Co-mobilization of VEGFR1+ haematopoietic stem and progenitor cells facilitate the incorporation of CEPs into functional tumour neo-vessels. Mobilization of CEPs and pro-angiogenic haematopoietic cells from bone marrow is a dynamic process that requires angiogenic-factor-mediated activation of metalloproteinases (MMPs), specifically MMP-9, which lead to the release of soluble KIT ligand (sKitL). sKitL promotes the proliferation and motility of CEPs and haematopoietic cells within the bone-marrow microenvironment, thereby laying the framework for their mobilization to the peripheral circulation. Inhibition of either VEGFR1 or VEGFR2 signalling can only partially block tumour angiogenesis and growth. Conversely, simultaneous inhibition of VEGFR1 and VEGFR2 signalling results in impaired mobilization and recruitment of VEGFR1+ haematopoietic cells and VEGFR2+ CEPs to the tumour vasculature, and is highly effective in retarding the growth of certain tumours. Characterization and quantification of VEGFR2+CEPs and VEGFR1+ haematopoietic cells in the peripheral blood, and plasma levels of VEGF, sKitL, MMP-9 and placental growth factor might lead to their use as surrogate markers for assessing the response to therapy or progression of certain malignancies. Moreover, factors that are involved in the mobilization and incorporation of CEPs and pro-angiogenic haematopoietic cells provide new targets to block tumour angiogenesis and growth.