Loss of expression of the recycling receptor, FcRn, promotes tumor cell growth by increasing albumin consumption

Abstract

Tumor cells rely on high concentrations of amino acids to support their growth and proliferation. Although increased macropinocytic uptake and lysosomal degradation of the most abundant serum protein, albumin, in Ras-transformed cells can meet these demands, it is not understood how the majority of tumor cells that express wild type Ras achieve this. In the current study we reveal that the neonatal Fc receptor, FcRn, regulates tumor cell proliferation through the ability to recycle its ligand, albumin. By contrast with normal epithelial cells, we show that human FcRn is present at very low or undetectable levels in the majority of tumor cell lines analyzed. Remarkably, shRNA-mediated ablation of FcRn expression in an FcRn-positive tumor cell line results in a substantial growth increase of tumor xenografts, whereas enforced expression of this receptor by lentiviral transduction has the reverse effect. Moreover, intracellular albumin and glutamate levels are increased by the loss of FcRn-mediated recycling of albumin, combined with hypoalbuminemia in tumor-bearing mice. These studies identify a novel role for FcRn as a suppressor of tumor growth and have implications for the use of this receptor as a prognostic indicator and therapeutic target.

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

“…Lower serum ALB may indicate that an individual has lower FcRn levels, resulting in higher ALB CL by catabolism; likewise, an individual with lower FcRn levels might be expected to exhibit higher CL of any administered IgG mAb. Recent data from preclinical studies showed that loss of expression of the recycling receptor, FcRn, promotes tumour cell growth by increasing albumin consumption, which shows how FcRn and ALB can be correlated. However, if there is an association between FcRn levels and disease severity, it still remains to be determined.…”

Single Protein Encapsulated Doxorubicin as an Efficacious Anticancer Therapeutic

“…An additional advantage of SPEDOX is cancer targeting, based on the hFcRn‐mediated HSA recycling mechanism. [ 21,35,36 ] If a cancer cell expresses less hFcRn than its normal counterpart, SPEDOX recycling would be less efficient, leading to increased endocytosis of SPEDOX into the cancer cell. DOX may be released from SPEDOX by different mechanisms, such as dissociation and HSA degradation, leading to higher free DOX concentration in the cancer cells.…”

Lack of FcRn Impairs Natural Killer Cell Development and Functions in the Tumor Microenvironment

“…Second, we reported FcRn mRNA and protein levels in both lung cancerous tissue and non-cancerous tissue associated with favorable prognosis in non-small cell lung cancer ( 13 ). Third, studies involving neoplastic cells expressing different levels of FcRn showed that FcRn-mediated recycling of albumin reduced tumor cell growth and proliferation ( 14 ).…”