Immune-mediated ECM depletion improves tumour perfusion and payload delivery.

Autor: Yeow YL; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Kotamraju VR; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Wang X; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Chopra M; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Azme N; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Wu J; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Schoep TD; Telethon Kids Institute, Subiaco, WA, Australia., Delaney DS; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Feindel K; Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, Perth, WA, Australia., Li J; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Kennedy KM; Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, WA, Australia., Allen WM; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia.; Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, WA, Australia., Kennedy BF; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia.; Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, WA, Australia., Larma I; Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, Perth, WA, Australia., Sampson DD; Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, Perth, WA, Australia.; Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, WA, Australia., Mahakian LM; Department of Biomedical Engineering, University of California Davis, Davis, CA, USA., Fite BZ; Department of Biomedical Engineering, University of California Davis, Davis, CA, USA., Zhang H; Department of Biomedical Engineering, University of California Davis, Davis, CA, USA., Friman T; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Mann AP; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Aziz FA; Sir Charles Gairdner Hospital, Perth, WA, Australia., Kumarasinghe MP; PathWest Laboratory Medicine, QE2 Medical Centre, Perth, WA, Australia., Johansson M; Sir Charles Gairdner Hospital, Perth, WA, Australia., Ee HC; Sir Charles Gairdner Hospital, Perth, WA, Australia., Yeoh G; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Mou L; Sir Charles Gairdner Hospital, Perth, WA, Australia., Ferrara KW; Department of Biomedical Engineering, University of California Davis, Davis, CA, USA., Billiran H; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Ganss R; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia., Ruoslahti E; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Hamzah J; Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2019 Dec; Vol. 11 (12), pp. e10923. Date of Electronic Publication: 2019 Nov 11.
DOI: 10.15252/emmm.201910923
Abstrakt: High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.
(© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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