Test Article

Abstract

2-microglobulin ( 2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. 2-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, 2-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 2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that 2-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 2-m have remarkable tumoricidal activity in cancer, through 2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, -catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of 2-m and 2-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 2-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.Keywords: Anti-2-m antibody, apoptosis, 2-microglobulin ( 2-m), osteomimicry. INTRODUCTION2-microglobulin ( 2-m), a well-known housekeeping gene, is a nonglycosylated protein with a low molecular weight of 12-kDa. This 99-amino acid residue protein is synthesized by all nucleated cells. It has been identified as a major structural component of amyloid fibrils deposited in dialysis-related amyloidosis, a common and serious complication in patients receiving hemodialysis for more than 10 years [1, 2]. 2-m forms a small invariable light chain subunit of the major histocompatibility complex (MHC) class I antigen, also known as human leukocyte antigen (HLA), on the cell surface of nucleated cells. 2-m is an important structural protein in the regulation of host immune recognition of self and non-self antigens by CD8 + T lymphocytes and for immunoglobulin transport and iron metabolism [3][4][5][6]. Some animal studies have reported that even when no MHC class I antigens could be detected on cells and the animals were grossly deficient in CD4 -CD8 + T cells, which normally mediate cytotoxic T cell function, the homozygotes appeared normal [7,8]....