Our intricate in vitro and in vivo experiments in multiple colon cancer settings for CXCR4 gain and loss of function studies demonstrate that CXCR4 intracellular protein but not its CXCL12 mediated signals modulate chemotherapy resistance and tumorigenic potential via inversely regulating the expression of DR5. This evidence concerns the gene TNFRSF10B and malignant colon neoplasm.