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 t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-06, Vol.275 (22), p.16666-16672
Main Authors: Fedarko, Neal S., Fohr, Bert, Robey, Pamela G., Young, Marian F., Fisher, Larry W.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
bone sialoprotein
complement factor H
Complement Factor H - metabolism
Complement System Proteins - immunology
Humans
Integrin-Binding Sialoprotein
Mice
Molecular Sequence Data
Neoplasms - immunology
Neoplasms - metabolism
Neoplasms - pathology
Osteopontin
Protein Binding
Sialoglycoproteins - metabolism
sialoproteins
Tumor Cells, Cultured
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Summary: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 αVβ3 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M001123200