Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack

Metastatic cancer cells, like trophoblasts of the developing placenta, are invasive and must escape immune surveillance to survive. Complement has lon g been thought to play a significant role in the tumor surveillance mechani sm. Bone sialoprotein (BSP) and osteopontin (OPN, ETA-1) are expressed by t rophoblasts and are strongly up-regulated by many tumors. Indeed, BSP has b een shown to be a positive indicator of the invasive potential of some tumo rs. In this report, we show that BSP and OPN form rapid and tight complexes with complement Factor H. Besides its key role in regulating complement-me diated cell lysis, Factor H also appears to play a role when "hijacked'' by invading organisms in enabling cellular evasion of complement, me have inv estigated whether BSP and OPN may play a similar role in tumor cell complem ent evasion by testing to see whether these glycoproteins could promote tum or cell survival. Recombinant OPN and BSP can protect murine erythroleukemi a cells from attack by human complement as web as human MCF-7 breast cancer cells and U-266 myeloma cells from attack by guinea pig complement. The me chanism of this gain of function by tumor cell expression of BSP or OPN has been defined using specific peptides and antibodies to block BSP and OPN p rotective activity. The expression of BSP and OPN in tumor cells provides a selective advantage for survival via initial binding to alpha(V)beta(3) in tegrin (both) or CD44 (OPN) on the cell surface, followed by sequestration of Factor H to the cell surface and inhibition of complement-mediated cell lysis.