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

Key Points

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.

Abstract

Tumours recruit neighbouring blood vessels and vascular endothelial cells to support their own blood supply. Recent evidence has indicated, however, that tumours are also capable of mobilizing bone-marrow-derived endothelial precursor cells, inducing them to migrate to the tumour and become incorporated into the developing vasculature. Tumour-derived angiogenic factors promote the recruitment of these cells, which include circulating endothelial progenitor cells and haematopoietic stem and progenitor cells. As clinical trials with anti-angiogenic agents have been confronted with therapeutic hurdles, inhibiting the recruitment of these vascular precursors might provide a novel approach to blocking tumour angiogenesis.

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Figure 1: Contribution of bone-marrow-derived cells to tumour angiogenesis.
Figure 2: Phenotypic and differentiation characteristics of CEPs.
Figure 3: Human-derived circulating endothelial progenitor cells contribute to tumour angiogenesis.
Figure 4: Haematopoietic stem, progenitors and precursor cells co-mobilize with CEPs.
Figure 5: MMP-9-mediated release of sKitL is necessary for the mobilization of CEPs and haematopoietic stem cells and progenitors.

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Acknowledgements

This work was supported by grants from the National Heart, Lung and Blood Institute, the American Cancer Society, the Leukemia and Lymphoma Society, the Doris Duke Charitable Foundation, the Children's Brain Tumor Foundation, the National Cancer Institute and Angiogenex.

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Correspondence to Shahin Rafii.

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BDNF

CXCR4

FGF2

G-CSF

GM-CSF

Id1

Id3

IGF

c-KIT

Mmp9

MMP-9

PDGF

PECAM

Plgf

PlGF

prominin-A

SCA1

S-endo-1

sKitL

thrombospondin-1

TNF-α

TPO

VE-cadherin

VEGFA

VEGFB

VEGFC

VEGFD

VEGFR1

VEGFR2

VEGFR3

von Willebrand factor

FURTHER INFORMATION

Memorial Sloan-Kettering — Id genes and angiogenesis

National Cancer Institute — understanding angiogenesis

Shahin Rafii's home page – Cornell Medical Center

Glossary

HAEMATOPOIETIC CELLS

Are either mature, differentiated precursor cells (like monocytes or macrophages), progenitor cells or immature haematopoietic stem cells.

HAEMATOPOIETIC STEM CELLS

Pluripotent cells that have the capacity to undergo self-renewal and stochastically differentiate into specific lineages, including the full compliment of erythroid, megakaryocytic, lymphoid and myelo-monocytic progenitors. Progenitors have limited proliferative capacity and have lost the potential to reconstitute haematopoiesis. Precursor cells, such as monocytes and macrophages, are terminally differentiated cells.

PERICYTES

The peri-endothelial cell layer, which stabilizes the vessel-wall integrity.

LEFT VENTRICULAR ASSIST DEVICES

(LVADs). Pulsatile, left ventricular assist devices for extended circulatory support that are implanted in patients that are awaiting cardiac transplantation. The blood-contacting surfaces of LVADs immediately colonize with haematopoietic and endothelial cells, generating a non-thrombogenic neo-intimal surface.

EMBRYOID BODIES

Clusters of totipotent cells that are formed as a result of in vitro culture of embryonic stem cells, in the absence of supportive stroma or growth factors. Exposure of embryoid bodies to specific growth factors induces differentiation of these cells.

LATE OUTGROWTH ENDOTHELIAL COLONIES

Incubation of bone-marrow-derived endothelial progenitors with growth factors such as VEGF, FGF2, IGF, collagen and fibronectin leads to the development of mature adherent endothelial colonies after 2 weeks. These are referred to as colony-forming units of endothelial cells (CFU-ECs). This is an unique characteristic of bone-marrow-derived endothelial progenitors, as mature vessel-wall-derived endothelial cells readily attach and proliferate, and are known as early outgrowth CFU-ECs.

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Rafii, S., Lyden, D., Benezra, R. et al. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?. Nat Rev Cancer 2, 826–835 (2002). https://doi.org/10.1038/nrc925

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