Immune-mediated ECM depletion improves tumour perfusion and payload delivery.
Animals
Cell Line
Cell Surface Display Techniques
Contrast Media
/ metabolism
Extracellular Matrix
/ metabolism
Female
Ferric Compounds
/ metabolism
Gadolinium
/ metabolism
Heterocyclic Compounds
/ metabolism
Humans
Male
Mice
Nanoparticles
/ metabolism
Organometallic Compounds
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
extracellular matrix
immune cells
peptide
solid tumour
tumour necrosis factor alpha
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
27
05
2019
revised:
26
09
2019
accepted:
09
10
2019
pubmed:
12
11
2019
medline:
28
4
2020
entrez:
12
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31709774
doi: 10.15252/emmm.201910923
pmc: PMC6895610
doi:
Substances chimiques
Contrast Media
0
Ferric Compounds
0
Heterocyclic Compounds
0
Organometallic Compounds
0
Tumor Necrosis Factor-alpha
0
gadoteridol
0199MV609F
ferric oxide
1K09F3G675
Gadolinium
AU0V1LM3JT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e10923Subventions
Organisme : Department of Health|National Health and Medical Research Council (NHMRC)
ID : APP1046507
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA188883
Pays : United States
Organisme : Cancer Council Western Australia
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA112356
Pays : United States
Organisme : University, State and Commonwealth Governments
Pays : International
Organisme : Department of Health|National Health and Medical Research Council (NHMRC)
ID : APP1121131
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA210553
Pays : United States
Organisme : Department of Health|National Health and Medical Research Council (NHMRC)
ID : APP1058073
Pays : International
Organisme : Center for Strategic Scientific Initiatives, National Cancer Institute (CSSI, NCI)
ID : CA188883
Pays : International
Organisme : HHS|NIH|National Cancer Institute (NCI)
ID : NIHCA210553
Pays : International
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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