Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors
Alexandra Abramsson, … , Per Lindblom, Christer Betsholtz
Alexandra Abramsson, … , Per Lindblom, Christer Betsholtz
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1142-1151. https://doi.org/10.1172/JCI18549.
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Article Oncology

Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors

Abstract

Tumor-infiltrating blood vessels deviate morphologically and biochemically from normal vessels, raising the prospect of selective pharmacological targeting. Current antiangiogenic approaches focus mainly on endothelial cells, but recent data imply that targeting pericytes may provide additional benefits. Further development of these concepts will require deeper insight into mechanisms of pericyte recruitment and function in tumors. Here, we applied genetic tools to decipher the function of PDGF-B and PDGF-Rβ in pericyte recruitment in a mouse fibrosarcoma model. In tumors transplanted into PDGF-B retention motif–deficient (pdgf-bret/ret) mice, pericytes were fewer and were partially detached from the vessel wall, coinciding with increased tumor vessel diameter and hemorrhaging. Transgenic PDGF-B expression in tumor cells was able to increase the pericyte density in both WT and pdgf-bret/ret mice but failed to correct the pericyte detachment in pdgf-bret/ret mice. Coinjection of exogenous pericytes and tumor cells showed that pericytes require PDGF-Rβ for recruitment to tumor vessels, whereas endothelial PDGF-B retention is indispensable for proper integration of pericytes in the vessel wall. Our data support the notion that pericytes serve an important function in tumor vessels and highlight PDGF-B and PDGF-Rβ as promising molecular targets for therapeutic intervention.

Authors

Alexandra Abramsson, Per Lindblom, Christer Betsholtz

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Figure 1

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Reduced pericyte recruitment and dilated vessels in tumors transplanted ...
Reduced pericyte recruitment and dilated vessels in tumors transplanted into pdgf-bret/ret mice. Double staining of endothelium (Pecam-1, red) and pericytes/VSMCs (SMA or NG2, green) in the vasculature of tumors and surrounding normal tissue of WT and pdgf-bret/ret mice. Recruitment of pericytes to tumor vessels was higher in WT (a) than in pdgf-bret/ret mice (b), and vessels in tumors grown on pdgf-bret/ret mice were morphologically abnormal and significantly dilated. Vessels in the surrounding dermal tissue show continuous coverage and circular arrangement of mural cells in both WT (c) and pdgf-bret/ret mice (d). NG2 staining of the pericytes demonstrated their close association with the endothelium in tumors in WT mice (e), whereas they were partially or completely detached from the tumor endothelium in pdgf-bret/ret mice (f and g, arrows). Bars: 50 μm.