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Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2007 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 12, 2606-2614 p.Article in journal (Refereed) Published
Abstract [en]

The aim of our study was to further explore the use of anti-angiogenic therapy targeting the vascular endothelial growth factor receptor (VEGFR) on endothelial cells while simultaneously targeting platelet-derived growth factor receptors (PDGFRs) on adjacent pericytes. B16 mouse melanoma tumors exogenously expressing PDGF-BB (B16/PDGF-BB) display higher pericyte coverage on the vasculature compared to the parental B16 tumors (B16/mock). These models were used to investigate the effects of combination therapy targeting VEGFR and PDGFR signaling on size-matched tumors. Combination therapy using 25 mg/kg/day of the VEGFR inhibitor PTK787 and 100 mg/kg/day of the PDGFR inhibitor STI571 decreased the tumor growth rate of both tumor types, but the inhibition was only significant in the B16/PDGF-BB tumors. Combination therapy induced vessel remodeling, primarily by reducing the vessel density in B16/mock tumors, and by reducing the vessel size in B16/PDGF-BB tumors. When analyzing the effects of combination therapy on tumor vessel pericytes, it was found to primarily reduce the subpopulation of alpha-smooth muscle actin and PDGFRbeta-positive pericytes partly detached from the tumor vessels, without affecting the number of pericytes closely attached to the endothelium, which also express desmin. Taken together, these data demonstrate an increased benefit of targeting both VEGFR and PDGFR pathways in B16/PDGF-BB tumors, and demonstrates that the increased tumor growth inhibition in this model is accompanied by a reduction in a specific subset of pericytes, characterized by being loosely attached to endothelial cells and negative for the pericyte marker desmin.

Place, publisher, year, edition, pages
2007. Vol. 121, no 12, 2606-2614 p.
Keyword [en]
Pericytes, anti-angiogenic therapy, PDGF, VEGF, tumor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-119798DOI: 10.1002/ijc.22999ISI: 000251109000004PubMedID: 17691110OAI: oai:DiVA.org:uu-119798DiVA: diva2:300998
Available from: 2007-11-06 Created: 2007-11-06 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Combination Therapies Targeting PDGF and VEGF Signaling Pathways in Solid Tumors
Open this publication in new window or tab >>Combination Therapies Targeting PDGF and VEGF Signaling Pathways in Solid Tumors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are independently involved in several cancer-associated mechanisms including autocrine stimulation of cancer cells, stimulation of tumor angiogenesis and regulation of interstitial fluid pressure (IFP). The scope of this thesis was to investigate the combinatory effect of anti-VEGF and anti-PDGF treatment on tumor angiogenesis and tumor IFP.

Angiogenesis is a process of formation of blood vessels. Based on the tumors dependency on the blood vessels to supply them with oxygen and nutrients, several anti-angiogenic therapies have been tried and shown to have beneficial anti-tumor effects. More recently, anti-angiogenic treatment appeared to transiently “normalize” disorganized tumor vasculature and therefore to improve the uptake of cytotoxic agents.

In the first study, treatment was performed on two tumor models that differ only with regard to the degree of maturation of the vasculature, reflected by different number of pericytes that are the target for anti-PDGF treatment in these tumors. The aim was to study the role of pericyte coverage in protecting endothelial cells from anti-VEGF therapies. In the pericyte-rich tumor model the combination treatment gave a more efficient anti-angiogenic effect. Interestingly, it was only a subset of pericytes that was sensitive for the treatment.

In the second paper, the effect of anti-VEGF and anti-PDGF treatment on tumor IFP was measured. IFP is elevated in most solid tumors, which is linked to poor prognosis and higher recurrence rate. Additionally, this serves as a problem in ant-cancer therapies since it makes the uptake of cytotoxic agents inefficient. PDGF is known to actively regulate the IFP by regulating the contractile activity of fibroblasts, while VEGF regulates IFP primarily by affecting vessel leakiness. In the current study, combination of anti-VEGF and anti-PDGF therapies was shown to have an additive effect. However, the timing of administration of inhibitors appeared to be crucial. It was only short, but not long term combination treatment that further reduced IFP as compared to monotherapies. Surprisingly, the additive effect on IFP did not translate into an increased efficiency of chemotherapy when comparing combination treatment with monotherapies.

The last paper is a follow up of the first study, where it was shown that combination of anti-VEGF and anti-PDGF treatment affect the tumor vasculature. Here we investigated if the anti-angiogenic effect improves treatment efficiency of a cytotoxic agent. There was a significant effect of the combination of anti-VEGF and anti-PDGF on Taxol treatment efficiency in this Taxol resistant tumor model. However, the mechanism for the treatment effect and the relative contribution of the targeted vasculature in the outcome of the therapy remains to be determined, since tumor cells were also sensitized for Taxol in vitro.

In summary, we have shown that targeting of PDGF and VEGF signaling pathways simultaneously affect both vasculature and IFP to a higher extent than monotherapies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 527
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-119827 (URN)978-91-554-7735-6 (ISBN)
Public defence
2010-04-09, B22, Uppsala Biomedical Center (BMC), Husargatan 3, Uppsala, 09:00 (English)
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Available from: 2010-03-26 Created: 2010-03-02 Last updated: 2011-02-21Bibliographically approved

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Kłosowska-Wardega, AgnieszkaHeldin, Carl-HenrikHellberg, Carina

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