EMBO Molecular Medicine (Dec 2019)
Immune‐mediated ECM depletion improves tumour perfusion and payload delivery
- Yen Ling Yeow,
- Venkata Ramana Kotamraju,
- Xiao Wang,
- Meenu Chopra,
- Nasibah Azme,
- Jiansha Wu,
- Tobias D Schoep,
- Derek S Delaney,
- Kirk Feindel,
- Ji Li,
- Kelsey M Kennedy,
- Wes M Allen,
- Brendan F Kennedy,
- Irma Larma,
- David D Sampson,
- Lisa M Mahakian,
- Brett Z Fite,
- Hua Zhang,
- Tomas Friman,
- Aman P Mann,
- Farah A Aziz,
- M Priyanthi Kumarasinghe,
- Mikael Johansson,
- Hooi C Ee,
- George Yeoh,
- Lingjun Mou,
- Katherine W Ferrara,
- Hector Billiran,
- Ruth Ganss,
- Erkki Ruoslahti,
- Juliana Hamzah
Affiliations
- Yen Ling Yeow
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Venkata Ramana Kotamraju
- Cancer Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA
- Xiao Wang
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Meenu Chopra
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Nasibah Azme
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Jiansha Wu
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Tobias D Schoep
- Telethon Kids Institute Subiaco WA Australia
- Derek S Delaney
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Kirk Feindel
- Centre for Microscopy, Characterisation & Analysis The University of Western Australia Perth WA Australia
- Ji Li
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Kelsey M Kennedy
- Department of Electrical, Electronic & Computer Engineering School of Engineering The University of Western Australia Perth WA Australia
- Wes M Allen
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Brendan F Kennedy
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Irma Larma
- Centre for Microscopy, Characterisation & Analysis The University of Western Australia Perth WA Australia
- David D Sampson
- Centre for Microscopy, Characterisation & Analysis The University of Western Australia Perth WA Australia
- Lisa M Mahakian
- Department of Biomedical Engineering University of California Davis Davis CA USA
- Brett Z Fite
- Department of Biomedical Engineering University of California Davis Davis CA USA
- Hua Zhang
- Department of Biomedical Engineering University of California Davis Davis CA USA
- Tomas Friman
- Cancer Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA
- Aman P Mann
- Cancer Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA
- Farah A Aziz
- Sir Charles Gairdner Hospital Perth WA Australia
- M Priyanthi Kumarasinghe
- PathWest Laboratory Medicine QE2 Medical Centre Perth WA Australia
- Mikael Johansson
- Sir Charles Gairdner Hospital Perth WA Australia
- Hooi C Ee
- Sir Charles Gairdner Hospital Perth WA Australia
- George Yeoh
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Lingjun Mou
- Sir Charles Gairdner Hospital Perth WA Australia
- Katherine W Ferrara
- Department of Biomedical Engineering University of California Davis Davis CA USA
- Hector Billiran
- Cancer Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA
- Ruth Ganss
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- Erkki Ruoslahti
- Cancer Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA
- Juliana Hamzah
- Harry Perkins Institute of Medical Research Centre for Medical Research QEII Medical Centre The University of Western Australia Perth WA Australia
- DOI
- https://doi.org/10.15252/emmm.201910923
- Journal volume & issue
-
Vol. 11,
no. 12
pp. n/a – n/a
Abstract
Abstract 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.
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