Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels.
BACKGROUND
The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice.


METHODS
Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the α₉ integrin was determined.


RESULTS
o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the α₉ integrin was detected on both tumour cells and blood vessels. Potential active peptides from the α₉ binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth.


CONCLUSIONS
These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the α₉ integrin are likely involved.
The Forsyth Institute, 245 First Street, Cambridge, MA 02412, USA.
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Rittling
Arla Foods Ingredients Group P/S Sønderhøj 14 8260 Viby J, Denmark.
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Wejse
The Forsyth Institute, 245 First Street, Cambridge, MA 02412, USA.
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Yagiz
The Forsyth Institute, 245 First Street, Cambridge, MA 02412, USA.
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Warot
The Forsyth Institute, 245 First Street, Cambridge, MA 02412, USA.
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Hui
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D039001:Integrin alpha Chains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism; D053495:Osteopontin / Q000008:administration & dosage* / Q000097:blood; D010455:Peptides / Q000097:blood / Q000378:metabolism; D011485:Protein Binding
D039001:Integrin alpha Chains; D009842:Oligopeptides; D010455:Peptides; C084613:integrin alpha9; D053495:Osteopontin; C047981:arginyl-glycyl-aspartic acid