Expression of
alpha(6) integrin, a
laminin receptor, on
tumor cell surfaces is associated with reduced patient survival and increased
metastasis in a variety of
tumors. In
prostate cancer,
tumor extracapsular escape occurs in part via
laminin-coated nerves and vascular dissemination, resulting in clinically significant bone
metastases. We previously identified a novel form of
alpha(6) integrin, called alpha(6)p, generated by
urokinase-type plasminogen activator-dependent cleavage of the
laminin-binding domain from the
tumor cell surface. Cleavage increased
laminin-dependent migration. Currently, we used the known conformation sensitivity of
integrin function to determine if engagement of the extracellular domain inhibited
integrin cleavage and the extravasation step of
metastasis. We show that
alpha(6) integrin was present on prostate
carcinoma escaping the gland via nerves. Both endogenous and inducible levels of alpha(6)p were inhibited by engaging the extracellular domain of alpha(6) with
monoclonal antibody J8H. J8H inhibited
tumor cell invasion through
Matrigel. A severe combined immunodeficient mouse model of extravasation and bone
metastasis produced detectable, progressive osteolytic lesions within 3 weeks of intracardiac
injections. Injection of
tumor cells, pretreated with J8H, delayed the appearance of
metastases. Validation of the alpha(6) cleavage effect on extravasation was confirmed through a genetic approach using
tumor cells transfected with uncleavable
alpha(6) integrin. Uncleavable
alpha(6) integrin significantly delayed the onset and progression of osseous
metastases out to six weeks post-injection. The results suggest that
alpha(6) integrin cleavage permits extravasation of human
prostate cancer cells from circulation to bone and can be manipulated to prevent
metastasis.