Quantitative fluorescent profiling of VEGFRs reveals tumor cell and endothelial cell heterogeneity in breast cancer xenografts.
Bottom Line: Plasma membrane-localized vascular endothelial growth factor receptors (VEGFR) play a critical role in transducing VEGF signaling toward pro and antiangiogenic outcomes and quantitative characterization of these receptors is critical toward identifying biomarkers for antiangiogenic therapies, understanding mechanisms of action of antiangiogenic drugs, and advancing predictive computational models.Furthermore, when these ex vivo data are compared to in vitro data, we observe little to no VEGFRs on MDA-MB-231 cells, and the MDA-MB-231 VEGFR surface levels are not regulated by a saturating dose of VEGF.Overall, the quantification of these dissimilarities for the first time in tumor provides insight into the balance of modulatory (VEGFR1) and proangiogenic (VEGFR2) receptors.
Affiliation: Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, 61801.Show MeSH
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Mentions: Although it is apparent that the isolated cells display significant heterogeneity, trends can be observed from the ensemble-averaged data. The large cells show: consistently low levels of VEGFRs; tECs having a higher average surface-VEGFRs compared to the tumor cells; and the highest VEGFR-surface levels are seen at week 6 (Table 3). The small cells have a higher average level of VEGFRs compared to the large cells (Tables 3 and 4). The small tEC have a higher average surface-VEGFRs compared to the small tumor cells (Table 4). VEGFRs on the small tumor cells remain approximately constant at weeks 3 and 6 (Fig. 7A). However, early-stage tumors (week 3) present significantly higher surface VEGFR1 on small tEC, ∼15,000 surface-VEGFR1/tEC when compared to week 6, where VEGFR1 surface levels are reduced by 45% on small tEC to 8150 surface-VEGFR1/tEC (Fig. 7B). Overall, the average levels of VEGFR2 on small tEC are between ∼1200 and 1700 surface-VEGFR2/tEC at weeks 3 and 6 (Fig. 7B), and they are in fact similar to the surface levels of VEGFR2 on endothelial cells derived from mouse skeletal muscle, ∼1100–1700 surface-VEGFR2/EC 41.
Affiliation: Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, 61801.