Opioids increase bladder cancer cell migration via bradykinin B2 receptors.

Data relating opioid treatment and modification of cancer cell migration (a prerequisite of metastasis) both in vitro and in vivo are diverging. In the present report we show that opioids increase the migratory activity of bladder cancer cells (T24 and EJ) and we provide a new mechanistic insight, explaining (at least partially) their action: we report that the enhanced opioid-related cell migration is controlled (in the absence of opioid receptors) through their interaction with bradykinin B2 receptors. Indeed, in these cell lines, opioids increase migration, adhesion, spreading and invasion by re-arranging actin cytoskeleton, increasing MMP-2 and -9 secretion and triggering specific intracellular signaling cascades in a non-opioid receptor mediated manner. An interaction, albeit with low affinity, of opioids with the bradykinin B2 receptor is reported, resulting in the increase of migration, while B2 antagonists revert this action. A systematic assay of different human epithelial cancer cell lines confirmed that only the B2-positive/opioid receptor-negative bladder cancer cells present this opioid-related increased migration/invasive phenotype. We suggest that opioid administration in cancer patients should be re-evaluated, keeping in mind that they may have other beneficial (protection) or adverse effects (spreading of cancer cells), in spite of their unique role in pain relief.