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Specific targeting of PDGFR beta in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2020 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 10, no 3, p. 1122-1135Article in journal (Refereed) Published
Abstract [en]

PDGF-BB/PDGFR beta 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 PDGFR beta 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 PDGFR beta ATP binding site that allows specific targeting of PDGFR beta using the compound 1-NaPP1. To evaluate the impact of selective PDGFR beta inhibition of stromal cells on tumor growth we investigated four tumor cell lines with no or low PDGFR beta 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 PDGFR beta 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 PDGFR beta 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 PDGFR beta by either drug impaired tumor vascularization and also affected pericyte coverage; however, specific targeting of PDGFR beta 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 PDGFR beta 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 PDGFR beta signaling significantly inhibits tumor progression and angiogenesis depending on PDGF-BB expression. Our data suggest that targeting PDGFR beta in the tumor stroma could have therapeutic value in patients with high tumor PDGF-BB expression.

Place, publisher, year, edition, pages
IVYSPRING INT PUBL , 2020. Vol. 10, no 3, p. 1122-1135
Keywords [en]
Low molecular weight inhibitor, PDGFR beta, pericytes, tumor growth, angiogenesis
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-402371DOI: 10.7150/thno.37851ISI: 000503870400011PubMedID: 31938055OAI: oai:DiVA.org:uu-402371DiVA, id: diva2:1391139
Funder
Swedish Cancer Society, 2018/425Swedish Cancer Society, 2015/445Lars Hierta Memorial FoundationStiftelsen Längmanska kulturfondenAvailable from: 2020-02-03 Created: 2020-02-03 Last updated: 2020-02-03Bibliographically approved

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