Bacillus Calmette-Guerin Abrogates in Vitro Invasion and Motility of Human Bladder Tumor Cells via Fibronectin Interaction

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Abstract
Intravesical bacillus Calmette-Guerin (BCG) has been shown to be an effective treatment for superficial transitional cell carcinoma of the bladder (TCC). The mechanisms by which BCG limits tumor cell activity have thus far been unclear. We investigated the interaction between BCG and invasive human TCC cell line EJ in an in vitro invasion assay. We observed that BCG inhibited the invasion of EJ cells through an artificial basement membrane. In terms of the steps involved in tumor cell invasion, i.e. attachment, proteolysis, and motility, BCG was found to limit tumor cell motility. Attachment and proliferation of tumor cells were not affected by BCG. The effects of BCG on tumor cell migration were mediated by fibronectin (FN), a basement membrane glycoprotein component. Abrogation of BCG-FN-tumor cell interactions with anti-FN antibodies eliminated the ability of BCG to block tumor cell invasion. Fibronectin appears to link BCG and tumor cells via independent FN binding receptors to separate domains of the FN molecule. The molecular mechanism by which BCG may limit tumor cell motility may be its ability to protect against the formation of specific FN sequences as a result of protease cathepsin B digestion. A 31 kD and 27 kD FN band were absent from purified or tumor cell associated cathepsin B digestion when incubated in the presence of BCG, but present in the absence of BCG. Furthermore when purified from SDS polyacrylamide gel electrophoresis, the fragments were shown to have motility stimulating activity for the invasive EJ cells. These findings suggest that BCG functions as a potent inhibitor of tumor cell invasion. We conclude that BCG-fibronectin-tumor cell interactions may have a direct influence on the invasive mechanisms, such as motility, of tumor cells.