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
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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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Model for perivascular PDGF-B protein distribution in T241 tumors and it...
Model for perivascular PDGF-B protein distribution in T241 tumors and its effect on tumor vessel pericytes. WT PDGF-B protein has affinity for heparan-sulfate proteoglycans and other ECM molecules. Its expression by the endothelium is therefore expected to give rise to a depot or steep gradient of PDGF-B in the periendothelial compartment (upper left). This promotes a certain amount of pericyte recruitment, and moreover, the recruited pericytes become intimately associated with the abluminal surface of the endothelium. Additional PDGF-B protein secreted by the tumor cells (upper right) leads to additional pericyte recruitment, with retained association to the endothelium. In pdgf-bret/ret mice, the PDGF-B protein lacks the retention motif, and is therefore more freely diffusible following its release from the endothelial cells (lower left). The lower concentration or shallower gradient in the periendothelial compartment leads to reduced pericyte recruitment and defective investment of the pericytes in the microvessel wall. Additional PDGF-B protein secreted by the tumor cells (lower right) promotes the recruitment of higher numbers of pericytes, which remain abnormally associated with the endothelium.