A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers.

Both NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA) silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients.

A positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-alpha) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA know-down. The transactivation of c-Met on Axl or PDGFR-alpha in vitro was through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these RTKs was associated with poor patient survival (p < 0.05), and overexpression of c-Met/Axl/PDGFR-alpha or c-Met alone showed the most significant correlation with poor survival (p < 0.01).

In addition to c-Met, the cross-talk with Axl and/or PDGFR-alpha also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-alpha expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy.

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