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Published on: May 12, 2017
PTK787/ZK 222584 inhibits tumor growth promoting mesenchymal stem cells: kinase activity profiling as powerful tool
Berber D Roorda1, Arja Ter Elst, Sander H Diks
1Department of Pediatric Hematology/Oncology, University Medical Center Groningen, Groningen 9700 RB, Netherlands.
Abstract:
Bone marrow (BM)-derived mesenchymal stem cells (MSCs) have been shown to favor tumor growth, suggesting the relevance of pharmaceutical inhibition of MSCs for the treatment of malignancies. We tested the effect of PTK787/ZK 222584 (PTK) on the outgrowth of MSCs from human bone marrow-derived mononuclear cells (MNCs) and the migration and tube formation capacity of MSCs in vitro. PTK dose-dependently inhibited the outgrowth of BM-MSCs from BM-MNCs (LC50 1.12 microM PTK), while hematopoietic colony formation (HCF) was only slightly hampered (13 +/- 19% at 1 microM PTK, and stable at approximately 50% at higher concentrations of PTK). Addition of 10 microM PTK inhibited proliferation of MSCs by 74 +/- 6.6% compared to control (p < 0.0001) and increased apoptosis of MSCs by 63 +/- 7.7% (p < 0.01). In addition, upon addition of PTK, BM-MSCs showed impaired tube formation as well as reduced migration (52 +/- 19%, p = 0.006) compared to control. Pepchip array analysis revealed that PTK effectively inhibits activity of kinases involved in cell cycling (WEE1 and several cyclin dependent kinases), and migratory processes (including Rho kinase). In conclusion, we show that PTK impairs outgrowth, proliferation, migration and tube formation of human BM-MSCs. In addition, we show the usability of Pepchip array analysis as a powerful tool for kinase activity profiling in functional studies since the effect of PTK on the kinome profile of MSCs corresponds with the observed functional effects of PTK on proliferation and migration. Inhibition of BM-MSCs and their contribution to tumor growth may be an additional strategy for treatment of cancer in the future.
Insights
PTK787/ZK 222584 (PTK) inhibits bone marrow-derived mesenchymal stem cells (MSCs) outgrowth, proliferation, and migration. This suggests PTK as a potential therapeutic strategy for targeting MSCs in cancer treatment.
Area of Science:
- Oncology
- Stem Cell Biology
- Pharmacology
Background:
- Bone marrow (BM)-derived mesenchymal stem cells (MSCs) promote tumor growth, highlighting the need for pharmaceutical inhibition strategies in cancer therapy.
- Targeting MSCs is a promising approach to disrupt tumor progression and enhance anti-cancer treatments.
Purpose of the Study:
- To investigate the effects of PTK787/ZK 222584 (PTK) on the biological functions of human BM-MSCs.
- To evaluate PTK's potential as a therapeutic agent for inhibiting MSCs in the context of cancer treatment.
Main Methods:
- Assessed PTK's impact on BM-MSC outgrowth from bone marrow mononuclear cells (MNCs).
- Evaluated PTK's effects on MSC proliferation, apoptosis, migration, and in vitro tube formation.
- Utilized Pepchip array analysis to profile kinase activity inhibition by PTK in MSCs.
Main Results:
- PTK dose-dependently inhibited BM-MSC outgrowth (LC50 1.12 microM) with minimal impact on hematopoietic colony formation.
- PTK significantly reduced MSC proliferation (74%) and increased apoptosis (63%), while impairing migration (52%) and tube formation.
- Pepchip analysis confirmed PTK inhibited kinases involved in cell cycling and migration, correlating with observed functional effects.
Conclusions:
- PTK effectively inhibits the outgrowth, proliferation, migration, and tube formation of human BM-MSCs.
- PTK demonstrates potential as a therapeutic agent to inhibit MSCs, offering a novel strategy for cancer treatment.
- Pepchip array analysis is a valuable tool for kinase activity profiling in functional studies of drug effects on MSCs.
