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
SN - 0168-3659
VL - 322
SP - 53
EP - 63
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -