A synthetic antagonist to laminin inhibits the formation of osteolytic metastases by human melanoma cells in nude mice.
The mechanisms by which tumor cells metastasize to bone are not well understood. We have investigated the role of the basement membrane glycoprotein, laminin, in bone metastasis, since antagonists to laminin have been shown to inhibit the formation of lung metastases. We studied the formation of osteolytic metastases caused by a human tumor which is known to cause osteolysis and hypercalcemia in nude mice. We found that tumor-bearing nude mice developed hypercalcemia, cachexia, and characteristic osteolytic lesions throughout the skeleton after injection of this human melanoma cell line (A375) into the left ventricle. When we gave injections to nude mice with A375 cells which had been exposed to C(YIGSR)3-NH2, a laminin-derived synthetic peptide containing three linear sequences of YIGSR with an amino-terminal cysteine which competes with laminin for its receptor, we found a decrease in the formation of detectable osteolytic bone metastases. The tumor cells were incubated with the antagonist and then inoculated into nude mice which were administered the antagonist i.p. Hypercalcemia and cachexia were also decreased in tumor-bearing mice treated with the laminin antagonist. In contrast, laminin itself increased the number of osteolytic bone metastases, as has been shown for other tumor cells. These data suggest that laminin plays a role in the formation of osteolytic bone metastases in this model and that laminin antagonists may be useful in the prevention of bone metastases in some human tumors.
Nakai
M
M
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7877.
Mundy
G R
GR
Williams
P J
PJ
Boyce
B
B
Yoneda
T
T
D000273:Adipose Tissue / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000556:secondary*; D006352:Heart Ventricles; D006801:Humans; D007797:Laminin / Q000037:antagonists & inhibitors*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism; D009368:Neoplasm Transplantation; D010014:Osteolysis / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011859:Radiography
D007797:Laminin; D010446:Peptide Fragments; D010455:Peptides; C076990:laminin B1 (1363-1383); C076989:C(YIGSR)3-NH2