1. Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden.
2. Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
3. Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala University, Sweden.
4. Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
5. Department of Neuroscience, Uppsala University, Sweden.
* These authors contributed equally to the study.
PDGF-BB/PDGFRβ signaling plays an important role during vascularization by mediating pericyte recruitment to the vasculature, promoting the integrity and function of vessels. Until now it has not been possible to assess the specific role of PDGFRβ signaling in tumor progression and angiogenesis due to lack of appropriate animal models and molecular tools.
Methods: In the present study, we used a transgenic knock-in mouse strain carrying a silent mutation in the PDGFRβ ATP binding site that allows specific targeting of PDGFRβ using the compound 1-NaPP1. To evaluate the impact of selective PDGFRβ inhibition of stromal cells on tumor growth we investigated four tumor cell lines with no or low PDGFRβ expression, i.e. Lewis lung carcinoma (LLC), EO771 breast carcinoma, B16 melanoma and a version of B16 that had been engineered to overexpress PDGF-BB (B16/PDGF-BB).
Results: We found that specific impairment of PDGFRβ kinase activity by 1-NaPP1 treatment efficiently suppressed growth in tumors with high expression of PDGF-BB, i.e. LLC and B16/PDGF-BB, while the clinically used PDGFRβ kinase inhibitor imatinib did not suppress tumor growth. Notably, tumors with low levels of PDGF-BB, i.e. EO771 and B16, neither responded to 1-NaPP1 nor to imatinib treatment. Inhibition of PDGFRβ by either drug impaired tumor vascularization and also affected pericyte coverage; however, specific targeting of PDGFRβ by 1-NaPP1 resulted in a more pronounced decrease in vessel function with increased vessel apoptosis in high PDGF-BB expressing tumors, compared to treatment with imatinib. In vitro analysis of PDGFRβ ASKA mouse embryo fibroblasts and the mesenchymal progenitor cell line 10T1/2 revealed that PDGF-BB induced NG2 expression, consistent with the in vivo data.
Conclusion: Specific targeting of PDGFRβ signaling significantly inhibits tumor progression and angiogenesis depending on PDGF-BB expression. Our data suggest that targeting PDGFRβ in the tumor stroma could have therapeutic value in patients with high tumor PDGF-BB expression.
Keywords: Low molecular weight inhibitor, PDGFRβ, pericytes, tumor growth, angiogenesis