β2-Microglobulin-mediated Signaling as a Target for Cancer Therapy

Abstract

β2-microglobulin (β2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. β2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, β2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that β2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that β2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against β2-m have remarkable tumoricidal activity in cancer, through β2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, β-catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of β2-m and β2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding β2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.

Circulating Beta-2 Microglobulin and Risk of Cancer: The Atherosclerosis Risk in Communities Study (ARIC)

“…Under normal physiological conditions, some amount of Β2M may be secreted into circulation from cell surfaces or as a result of intracellular release (2–4) and is removed from blood predominantly by the kidneys (5). Thus, the net concentration of serum Β2M is determined by its generation and secretion into serum, as well as its elimination by the kidneys, so that serum B2M concentration increases with elevated turnover of cells and/or reduced kidney function (6).…”

Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis

“…Over-expression of β2M increases tumor growth and promotes migration and invasion of small lung cancer, prostate cancer, renal cancer, ovarian cancer, and breast cancer cells by the stimulation of epithelial-mesenchymal transition (EMT). In addition, β2M has multiple functions in tumor development and mediates tumorigenesis, metastasis and angiogenesis [13][14][15]. Previous studies demonstrated that β2M modulates its action in vitro via increased protein kinase A (PKA)/cyclic AMP-responsive element-binding protein (CREB) phosphorylation, VEGF expression, and cell survival, including the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathways in human renal carcinoma cells [16,17].…”

RANK-mediated signaling network and cancer metastasis

“…reported that HFE protein, a non-classical MHC class I member, interacts with β2-m to modulate iron homeostasis by interacting with the transferrin receptor (TFR) and its complex, TFRC, which together govern EMT and ROS in cancer cells. β2-m protected against the influx and accumulation of intracellular iron, and lower levels of intracellular iron activated HIF-1α and its target genes including EMT markers and VEGF [31,36]. Knocking down either the HFE protein or β2-m resulted in mesenchymal to epithelial transition (MET), a reversal of EMT, decreased cell proliferation and increased apoptosis in PCa cells [42].…”

“…β2-m activates intracellular signaling axes mediated by ERK and sterol regulatory element-binding protein-1 (SREBP-1), that drive lipogenesis and lipid and lipid raft-mediated signaling and could potentially enhance the survival of cancer cells [34]. These results together with the demonstration that β2-m-mediated multiple downstream converging signaling pathways, including AR, lipid, iron and ROS [31,36,42,43], could exert powerful influences on the fate of PCa cells and their clinical behavior.…”

“…Because genetic knockdown of β2-m or its receptor HFE drives the reversal of EMT with evidence of PCa cell death, we and others have employed anti-β2-m antibodies as reagents to treat both liquid [44,45] and solid [32,34,36,42] tumors in mice. While these antibodies have no observable effects on the growth of normal organs and cells, application of these antibodies caused remarkable remission of both liquid and solid tumors in experimental mice, compared to the effects of isotype-specific control antibodies [34,44,45].…”