Role of Autocrine Motility Factor in Osteolytic Metastasis.

Abstract : Autocrine motility factor (AMF) is a l25kDa dimeric protein with two distinct functions: Intracellularly, it is an essential, ubiquitously expressed glycolytic enzyme. Extracellularly, it is also found in the circulation of patients with cancer, particularly with advanced, metastatic disease. Release of the extracellular form is by an unknown mechanism, but the factor binds to a known receptor with high affinity and has a number of effects, including stimulation of cell motility and differentiation of monocytic cells. We show here that AMF is a potent stimulator of the formation of osteoclasts, cells which resorb bone. The effect is species-specific by about lOOX between mouse and human AMFs and their receptors. The dose-response is bell-shaped with maximum effects at 1ng/m1. In vitro mouse AMF induces RANK ligand expression in a bone marrow stromal line. RANK ligand is the central regulator of osteoclast formation. Cells secreting mouse AMF formed tumors in the muscles of nude mice and caused several dramatic effects compared to equal-sized control tumors: 1) Systemically, AMF secretion caused severe weight loss (cachexia). 2) Locally, AMF stimulated formation of disorganized new bone between the tumor and the surface of the femur. The data suggest that AMF is a novel stimulator of local changes in bone during metastasis and may also be a systemic mediator of cachexia, a serious complication of neoplasia.