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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Figure 6

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Exogenous PDGF-Rβ–deficient pericytes are not recruited by tumor vessels...
Exogenous PDGF-Rβ–deficient pericytes are not recruited by tumor vessels. MEFs were isolated from XlacZ4-positive WT or PDGF-Rβ–negative embryonic day 12.5 embryos and cultured in vitro (a and b). These cultures contained similar proportions of XlacZ4-positive cells (∼10%). T241 cells mixed with MEFs at a 1:9 ratio were injected subcutaneously onto the backs of WT mice. Cells expressing lacZ (pink) were found closely associated with endothelial cells (Pecam-1, brown) in tumors mixed with PDGF-Rβ–positive MEF cells (c, arrows) but not in tumors mixed with PDGF-Rβ–negative MEF cells (d). Triple staining shows that the recruited lacZ-positive MEF cells (e, arrowheads) also express SMA (green) and that the lacZ/SMA double-positive cells are tightly associated with the endothelium (brown) (e). Vessels in tumors mixed with PDGF-Rβ–negative MEF cells lack exogenous (lacZ-positive) pericytes but recruit endogenous (lacZ-negative, SMA-positive) pericytes, as expected (f, arrows). Prelabeling of MEF cultures with Pkh26 dye indicates the presence and similar distribution of PDGF-Rβ–positive and –negative MEF cells within the tumors (g and h). Bars: 100 μm (a and b), 50 μm (c, d, g, and h), and 20 μm (e and f).