β2-Microglobulin (β2M), a soluble factor secreted by cancer and host inflammatory cells, is associated with the presentation of heavy chain major histocompatibility complex (MHC) class I. In this communication, we characterized an unexpected role of β2M as a growth factor and signaling molecule in solid tumors. We showed β2M increased cell motility, migration and invasion in human tumor cells and promoted their epithelial to mesenchymal transition. β2M-mediated cell signaling promoted the growth, survival and osteomimicry of human prostate, breast, lung and renal cancer cells. We overexpressed β2M in human prostate (C4-2B), breast (MCF-7), renal (SN12C) and lung (H358) cancer cell lines using an expression plasmid cDNA encoding β2M (control cells were stably tranfected with neo expression construct) and correlated the levels of β2M expression with the anchorage-dependent and -independent growth of these cancer cell lines. We also evaluated the growth of these cancer cell lines in mice. β2M siRNA was constructed and delivered to cells or tumors to target the endogenous β2M mRNA using cationic SN liposome complexes with high transfection efficiency but low toxicity. Athymic male nu/nu mice bearing human prostate tumors in tibia or as bone powder implants were found to be highly responsive to the treatment of β2M siRNA liposome complexes. Prostate tumor growth was monitored by serum PSA or followed by real-time CCD camera for firefly luciferase bioluminescence. β2M was identified as a key mitogenic cell signaling molecule stimulating the growth of cancer cells in vitro and tumors in mice. β2M protein correlated with the invasiveness of several prostate cancer cell lines tested and expressed prevalently in human prostate cancer bone metastatic specimens. A β2M-siRNA-liposome complex inoculated into mouse bone bearing human prostate cancer induced massive cancer cell death. In conclusion, β2M, expressed by human prostate, breast, renal and lung cancer cells, had a previously unrecognized role as a mitogenic factor for cancer growth and bone metastasis. Targeting β2M signaling pathway with β2M siRNA could prove to be a promising approach for the treatment of local cancer growth and their distant metastases.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]