FcRn overexpression in human cancer drives albumin recycling and cell growth: a mechanistic basis for exploitation in targeted albumin-drug designs

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FcRn overexpression in human cancer drives albumin recycling and cell growth : a mechanistic basis for exploitation in targeted albumin-drug designs. / Larsen, Maja Thim; Mandrup, Ole A; Schelde, Karen Kræmmer; Luo, Yonglun; Sørensen, Karina Dalsgaard; Dagnæs-Hansen, Frederik; Cameron, Jason; Stougaard, Magnus; Steiniche, Torben; Howard, Kenneth A.

I: Journal of Controlled Release, Bind 322, 06.2020, s. 53-63.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{64951c7692344edd9ba5f433bc45b374,
title = "FcRn overexpression in human cancer drives albumin recycling and cell growth: a mechanistic basis for exploitation in targeted albumin-drug designs",
abstract = "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 FcRn-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 FcRn-driven albumin recruitment for increased cellular growth that has the potential to be exploited with high FcRn-binding albumin variants for targeted therapies.",
keywords = "Albumin, Cancer, Neonatal Fc receptor, Protein engineering, Targeted drug delivery",
author = "Larsen, {Maja Thim} and Mandrup, {Ole A} and Schelde, {Karen Kr{\ae}mmer} and Yonglun Luo and S{\o}rensen, {Karina Dalsgaard} and Frederik Dagn{\ae}s-Hansen and Jason Cameron and Magnus Stougaard and Torben Steiniche and Howard, {Kenneth A}",
year = "2020",
month = jun,
doi = "10.1016/j.jconrel.2020.03.004",
language = "English",
volume = "322",
pages = "53--63",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - FcRn overexpression in human cancer drives albumin recycling and cell growth

T2 - a mechanistic basis for exploitation in targeted albumin-drug designs

AU - Larsen, Maja Thim

AU - Mandrup, Ole A

AU - Schelde, Karen Kræmmer

AU - Luo, Yonglun

AU - Sørensen, Karina Dalsgaard

AU - Dagnæs-Hansen, Frederik

AU - Cameron, Jason

AU - Stougaard, Magnus

AU - Steiniche, Torben

AU - Howard, Kenneth A

PY - 2020/6

Y1 - 2020/6

N2 - 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 FcRn-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 FcRn-driven albumin recruitment for increased cellular growth that has the potential to be exploited with high FcRn-binding albumin variants for targeted therapies.

AB - 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 FcRn-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 FcRn-driven albumin recruitment for increased cellular growth that has the potential to be exploited with high FcRn-binding albumin variants for targeted therapies.

KW - Albumin

KW - Cancer

KW - Neonatal Fc receptor

KW - Protein engineering

KW - Targeted drug delivery

U2 - 10.1016/j.jconrel.2020.03.004

DO - 10.1016/j.jconrel.2020.03.004

M3 - Journal article

C2 - 32145268

VL - 322

SP - 53

EP - 63

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -