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Targeting of CCL2-CCR2-Glycosaminoglycan Axis Using a CCL2 Decoy Protein Attenuates Metastasis through Inhibition of
Marko Roblek1, Elisabeth Strutzmann2, Christina Zankl2
1Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, CH-8057 Zurich, Switzerland.
Abstract:
The CCL2-CCR2 chemokine axis has an important role in cancer progression where it contributes to metastatic dissemination of several cancer types (e.g., colon, breast, prostate). Tumor cell-derived CCL2 was shown to promote the recruitment of CCR2(+)/Ly6C(hi) monocytes and to induce vascular permeability of CCR2(+) endothelial cells in the lungs. Here we describe a novel decoy protein consisting of a CCL2 mutant protein fused to human serum albumin (dnCCL2-HSA chimera) with enhanced binding affinity to glycosaminoglycans that was tested in vivo. The monocyte-mediated tumor cell transendothelial migration was strongly reduced upon unfused dnCCL2 mutant treatment in vitro. dnCCL2-HSA chimera had an extended serum half-life and thus a prolonged exposure in vivo compared with the dnCCL2 mutant. dnCCL2-HSA chimera bound to the lung vasculature but caused minimal alterations in the leukocyte recruitment to the lungs. However, dnCCL2-HSA chimera treatment strongly reduced both lung vascular permeability and tumor cell seeding. Metastasis of MC-38GFP, 3LL, and LLC1 cells was significantly attenuated upon dnCCL2-HSA chimera treatment. Tumor cell seeding to the lungs resulted in enhanced expression of a proteoglycan syndecan-4 by endothelial cells that correlated with accumulation of the dnCCL2-HSA chimera in the vicinity of tumor cells. These findings demonstrate that the CCL2-based decoy protein effectively binds to the activated endothelium in lungs and blocks tumor cell extravasation through inhibition of vascular permeability.
Insights
A novel decoy protein targeting the CCL2-CCR2 pathway effectively reduced cancer cell metastasis by inhibiting lung vascular permeability and tumor cell extravasation. This offers a promising strategy for preventing cancer spread.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- The CCL2-CCR2 chemokine axis drives cancer progression and metastasis in various cancers.
- CCL2 recruits monocytes and increases vascular permeability, facilitating tumor cell dissemination.
- Targeting this axis is crucial for developing novel anti-metastatic therapies.
Purpose of the Study:
- To develop and evaluate a novel decoy protein (dnCCL2-HSA chimera) targeting the CCL2-CCR2 pathway.
- To assess the efficacy of dnCCL2-HSA in preventing tumor cell metastasis in vivo.
- To investigate the mechanism by which the decoy protein inhibits tumor cell extravasation.
Main Methods:
- Development of a dnCCL2-HSA chimera with enhanced glycosaminoglycan binding.
- In vitro assessment of monocyte-mediated tumor cell transendothelial migration.
- In vivo evaluation of dnCCL2-HSA in mouse models of lung metastasis.
- Analysis of lung vascular permeability, leukocyte recruitment, and tumor cell seeding.
- Correlation of decoy protein accumulation with syndecan-4 expression in lung vasculature.
Main Results:
- dnCCL2-HSA chimera significantly reduced monocyte-mediated tumor cell migration in vitro.
- The chimera exhibited prolonged serum half-life and bound to lung vasculature in vivo.
- dnCCL2-HSA treatment markedly decreased lung vascular permeability and tumor cell seeding.
- Metastasis of MC-38GFP, 3LL, and LLC1 cells was significantly attenuated.
- Decoy protein accumulation correlated with syndecan-4 expression on activated endothelial cells.
Conclusions:
- The CCL2-based decoy protein (dnCCL2-HSA) effectively inhibits tumor cell extravasation.
- dnCCL2-HSA acts by binding to activated lung endothelium and reducing vascular permeability.
- This novel therapeutic strategy shows significant potential in blocking cancer metastasis.
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