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 long been thought to play a significant role in the tumor surveillance mechanism. Bone sialoprotein (BSP) and osteopontin (OPN, ETA-1) are expressed by trophoblasts and are strongly up-regulated by many tumors. Indeed, BSP has been shown to be a positive indicator of the invasive potential of some tumors. 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-mediated cell lysis, Factor H also appears to play a role when "hijacked" by invading organisms in enabling cellular evasion of complement. We have investigated whether BSP and OPN may play a similar role in tumor cell complement evasion by testing to see whether these glycoproteins could promote tumor cell survival. Recombinant OPN and BSP can protect murine erythroleukemia cells from attack by human complement as well as human MCF-7 breast cancer cells and U-266 myeloma cells from attack by guinea pig complement. The mechanism 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 protective activity. The expression of BSP and OPN in tumor cells provides a selective advantage for survival via initial binding to alpha(V)beta(3) integrin (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.
Fedarko
N S
NS
Division of Geriatrics, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA. ndarko@welch.jhu.edu
Fohr
B
B
Robey
P G
PG
Young
M F
MF
Fisher
L W
LW
D000595:Amino Acid Sequence; D000818:Animals; D017242:Complement Factor H / Q000378:metabolism*; D003165:Complement System Proteins / Q000276:immunology*; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin; D011485:Protein Binding; D012795:Sialoglycoproteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C493495:CFH protein, human; C546871:IBSP protein, human; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D017242:Complement Factor H; D003165:Complement System Proteins