Internalization of Mycobacterium bovis, Bacillus Calmette Guerin, by bladder cancer cells is cytotoxic

Abstract

Abstract. Instillation of Bacillus Calmette Guerin (BCG) into the bladder is the standard treatment for superficial bladder cancer. It leads to a local inflammatory response due to the release of cytokines and influx of immune cells to the tumor site. Although the presence of an intact immune system is an essential criterion for successful therapy, attachment of the bacteria to the bladder urothelial is just as important. The purpose of our study is to determine the role of bacterial internalization by epithelial cells. Transfection of the α5 integrin gene into the BCG unresponsive bladder cancer cell line, RT4, caused an increase in bacterial uptake and also increased cell death. Treatment of cells with cycloheximide did not prevent bacterial internalization but blocked its cytotoxic effect suggesting that unlike cell death, the process of bacterial internalization does not require new protein synthesis. Our data also show that the bacteria secretory products can prevent its own internalization. The extract prepared from lyophilized BCG altered the phosphorylation status of the focal adhesion kinase which is responsible for cellular endocytosis. Therefore, bacterial phosphatases may be present in the bacterial extract. Their activity may inhibit BCG internalization. Thus washing the reconstituted bacteria to remove the enzymes before instillation into the bladder might improve the therapeutic outcome of intravesical BCG therapy.

Oncogenic Activation of Pak1-Dependent Pathway of Macropinocytosis Determines BCG Entry into Bladder Cancer Cells

“…Direct and indirect immune mechanisms have been postulated to play a role (4), as have direct cytotoxic effects on the tumor cell (5). BCG attachment to tumor cells, leading to internalization and processing of the mycobacterium, likely plays a crucial role in activation of BCG-mediated anti-tumor activity (6-8).…”

Inhibition of Mycobacterial Infection by the Tumor Suppressor PTEN

“…This is due in part to the fact that its mechanism of action is not well understood. Direct and indirect immune mechanisms have been hypothesized to play a role (13,14) as have direct cytotoxic effects of BCG (15). Whatever the mechanism of action, it does seem clear that BCG interaction with tumor cells, leading to internalization and processing of the mycobacterium, plays a * This work was supported, in whole or in part, by National Institutes of Health crucial role in activation of BCG-mediated anti-tumor activity (16 -19).…”

Mechanism responsible for the antitumor effect of BCG-CWS using the LEEL method in a mouse bladder cancer model

“…Some reports of in vitro experiments showed that the exposure of BCG to bladder cancer cells decreased cell growth and induced cell death [17][18][19]. However, this type of cytotoxicity was induced only with very high ratios of BCG to bladder cancer cells.…”

“…It has been reported that the exposure of BCG to bladder cancer cells resulted in a decreased cell growth and the induction of cell death [17][18][19]. …”