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.