FcRn overexpression in human cancer drives albumin recycling and cell growth; a mechanistic basis for exploitation in targeted albumin-drug designs.
Albumin
Cancer
Neonatal Fc receptor
Protein engineering
Targeted drug delivery
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
10 06 2020
10 06 2020
Historique:
received:
16
12
2019
revised:
11
02
2020
accepted:
03
03
2020
pubmed:
8
3
2020
medline:
22
6
2021
entrez:
8
3
2020
Statut:
ppublish
Résumé
Albumin accumulation in tumours could reflect a role of albumin in transport of endogenous nutrient cargos required for cellular growth and not just a suggested source of amino acids; a role driven by albumin engagement with its cognate cellular recycling neonatal Fc receptor. We investigate the hypothesis that albumin cellular recruitment is increased by higher human FcRn (hFcRn) expression in human cancer tissue that provides the mechanistic basis for exploitation in albumin-based drug designs engineered to optimise this process. Eight out of ten different human cancer tissue types screened for hFcRn expression by immunohistochemistry (310 samples) exhibited significantly higher hFcRn expression compared to healthy tissues. Accelerated tumour growth over 28 days in mice inoculated with hFcRn-expressing HT-29 human colorectal cancer cell xenografts, compared to CRISPR/Cas9 hFcRn-knockout HT-29, suggests a hFcRn-mediated tumour growth effect. Direct correlation between hFcRn expression and albumin recycling supports hFcRn-mediated diversion of albumin from lysosomal degradation. Two-fold increase in accumulation of fluorescent labelled high-binding hFcRn albumin, compared to wild type albumin, in luciferase MDA-MB-231-Luc-D3H2LN breast cancer xenografts was shown. This work identifies overexpression of hFcRn in several human cancer types with mechanistic data suggesting hFcRn-driven albumin recruitment for increased cellular growth that has the potential to be exploited with high hFcRn-binding albumin variants for targeted therapies.
Identifiants
pubmed: 32145268
pii: S0168-3659(20)30151-6
doi: 10.1016/j.jconrel.2020.03.004
pii:
doi:
Substances chimiques
Histocompatibility Antigens Class I
0
Receptors, Fc
0
Serum Albumin, Human
ZIF514RVZR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
53-63Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Albumedix is a producer of recombinant albumin and markets the Veltis® technology for half-life extension of drugs using human albumin variants. Maja Thim Larsen, Frederik Dagnæs-Hansen, Jason Cameron and Kenneth A. Howard are inventors of patent family WO 2018/082758 titled Identification and treatment of tumours characterized by an overexpression of the neonatal Fc receptor. Jason Cameron is an inventor on patent family WO 201105/1489 titled ALBUMIN VARIANTS.