title: 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.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nomura
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Sajni
authors.initials: S
authors.lastname: Josson
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Mimata
authors.affiliation: Department of Urology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan. TAKE@oita-u.ac.jp.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D058750:Epithelial-Mesenchymal Transition; D005805:Genes, MHC Class I; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001613:beta 2-Microglobulin