Objective:Semaphorin 4D (Sema4D) acts as a regulator for axon guidance in central nervous system development. However, new evidence indicates that Sema4D has a previously unrecognized function, namely, compensatory angiogenic factor. This study aimed to investigate the effect of Sema4D on tumor growth and vascularity of colorectal carcinoma (CRC) in nude mice. Meth-ods:Sema4D was knocked down in CRC cells by infecting the cells with lentiviruses coding for Sema4D shRNA. Two groups of cells, namely, those infected with control viruses and those infected with Sema4D shRNA viruses, were subjected to migration assay to test their ability induce endothelial cell migration. The two cell groups were subcutaneously injected into nude mice. Tumor growth was documented, and the tumors harvested from the mice were subjected to immunohistochemistry or immuno fl uorescence analyses. Re-sults:In vitro migration assay results indicated that media conditioned by HCT-116 cells infected with Sema4D shRNA lentiviruses in-duced low endothelial cell migration. The two groups of subcutaneously inoculated cells showed 100%tumorigenicity. However, tumor growth rates were significantly different between the two groups. Xenografts in which Sema4D was downregulated showed marked re-duction in tumor size and vascularity. Conclusion:Cancer cells may highly express Sema4D to trigger net neo-angiogenesis and gener-ate a tumor blood supply system. Thus, Sema4D could potentially be a target in anti-angiogenic therapy of CRC patients.