Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors

Abstract

The precise mechanisms whereby anti-angiogenesis therapy blocks tumour growth or causes vascular toxicity are unknown. We propose that endothelial cells establish a vascular niche that promotes tumour growth and tissue repair not only by delivering nutrients and O2 but also through an 'angiocrine' mechanism by producing stem and progenitor cell-active trophogens. Identification of endothelial-derived instructive angiocrine factors will allow direct tumour targeting, while diminishing the unwanted side effects associated with the use of anti-angiogenic agents.

Figure 1. The vascular niche supports the expansion of stem and progenitor cells as well as their malignant counterparts

a | By expressing angiocrine factors and producing extracellular matrix (ECM), endothelial cells and endothelial progenitor cells (EPCs) establish a microenvironment, referred to as the vascular niche, which supports the expansion of normal and malignant stem and progenitor cells. b | Establishment of the vascular niche by the bone marrow sinusoidal endothelial cells. The confocal image shows a cross-section of the bone marrow taken from transgenic Notch reporter mice 7 days after sublethal irradiation with 6.5 Gy. Regenerating Notch-activated green fluorescent protein (GFP)⁺ haematopoietic stem and progenitor cells (green fluorescence) could be detected in the proximity of VE-cadherin⁺ Notch ligand⁺ sinusoidal endothelial cells (red staining). Therefore, angiocrine factors, such as Notch ligands, reconstitute haematopoiesis. c | Vascular endothelial growth factor A (VEGFA)- or fibroblast growth factor 2 (FGF2)-activated endothelial cells promote the proliferation and lineage-specific differentiation of normal cells by release of angiocrine factors (FGFs, BMPs, jagged 1 and jagged 2) and direct cellular contact. d | Identical pathways to those described in (c) affect malignant stem and progenitor cells. e | The mature progeny of stem cells, such as megakaryocytes, enforce a quiescent state in the endothelial cells by inhibiting their angiogenic activity through the release of anti-angiogenic factors, such as thrombospondins, which in turn promotes stem cell quiescence. BDNF, bone-derived neurotrophic factor; BMP, bone morphogenetic protein; PEDF, pigment epithelium-derived factor; TGFβ, transforming growth factor-β. Bar represents 50 μm.

Figure 2. The vascular niche supports the progression of leukaemic cells

The prototypical angiogenic factor vascular endothelial growth factor A (VEGFA) released by leukaemic cells (green fluorescent protein⁺ cells in (a) and infiltrating cells in (b)) activates the tyrosine kinase VEGF receptor 2 (VEGFR2) expressed on the endothelial cells and this promotes the proliferation of VE-cadherin⁺ vessels in the bone marrow (a, arrows) and liver (b, arrows). In vitro E4ORF1⁺ primary endothelial cells (PECs) support the long term expansion of HL60 leukaemic cells in serum- and cytokine-free conditions (c), and in the absence of the E4ORF1⁺ primary endothelial cells HL60 leukaemic cells undergo cell death (c). The mechanism by which endothelial cells support the proliferation of the leukaemic cells is through the VEGFA–VEGFR2-mediated upregulation of the pro-leukaemic factors (d) leading to the uncontrolled proliferation of the leukaemic cells. G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage-colony stimulating factor; IL-6, interleukin-6; KITL, KIT ligand. Part (c) of this figure is reproduced from ref. .

Figure 3. Activation of VEGFR2 tyrosine kinase signalling pathways is essential for the regeneration and remodelling of the sinusoidal endothelial cells in the bone marrow

Timely regeneration of the sinusoidal endothelial cells supports regeneration of the haematopoietic stem and progenitor cells, guaranteeing prompt reconstitution of haematopoiesis after treatment with myeloablative chemotherapy and irradiation. As such, bone marrow sinusoidal endothelial cells establish a vascular niche that, through the release of angiocrine factors, promotes the reconstitution of the haematopoietic stem and progenitor cells. VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2.