Receptor tyrosine kinases (RTK) and their
ligands control critical
biologic processes, such as cell proliferation, migration, and differentiation. Aberrant expression of these receptor
kinases in
tumor cells alters multiple downstream signaling cascades that ultimately drive the malignant phenotype by enhancing
tumor cell proliferation, invasion,
metastasis, and angiogenesis. As observed in human
glioblastoma (hGBM) and other
cancers, this dysregulation of RTK networks correlates with poor patient survival.
Epidermal growth factor receptor (EGFR) and c-Met, two well-known receptor
kinases, are coexpressed in multiple
cancers including hGBM, corroborating that their downstream signaling pathways enhance a malignant phenotype. The integration of c-Met and EGFR signaling in
cancer cells indicates that treatment regimens designed to target both receptor pathways simultaneously could prove effective, though resistance to
tyrosine kinase inhibitors continues to be a substantial obstacle. In the present study, we analyzed the antitumor efficacy of EGFR inhibitors
erlotinib and
gefitinib and c-Met inhibitor
PHA-665752, along with their respective small hairpin RNAs (shRNAs) alone or in combination with human umbilical cord blood stem cells (hUCBSCs), in
glioma cell lines and in animal xenograft models. We also measured the effect of dual inhibition of EGFR/c-Met pathways on invasion and wound healing. Combination treatments of hUCBSC with
tyrosine kinase inhibitors significantly inhibited invasion and wound healing in U251 and 5310 cell lines, thereby indicating the role of hUCBSC in inhibition of RTK-driven cell behavior. Further, the EGFR and c-Met localization in
glioma cells and hGBM clinical specimens indicated that a possible cross talk exists between EGFR and c-Met signaling pathway.