Abstract
Developmentally regulated endothelial cell locus-1 (Del1) is an embryonic angiogenic factor expressed in early embryonic endothelial cells, but recently has been found to be expressed in some forms of cancers including colon and breast cancers, and melanoma, and human cancer cell lines. Overexpression of Del1 accelerates tumor growth by enhancing vascular formation, implying Del1 may be a potential target for anti-angiogenic cancer therapy. The study aims to investigate whether downregulation of Del1 could inhibit the growth of tumors established in nude Balb/c mice by subcutaneous implantation of human LS-174T colon cancer cells. The shRNA expression vectors targeting human Del1, and vascular endothelial growth factor (VEGF) were constructed. Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro. Gene transfection of VEGF-shRNA downregulated expression of both VEGF and Del1 in LS-174T cells in vivo and in vitro. Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation. Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer.
Highlights
Colon cancer is the fifth cause of cancer-related death in developed countries, and its incidence is rising at an alarming rate in developing countries [1]
Expression of Developmentally regulated endothelial cell locus-1 (Del1) in colon cancer cell lines and tissues from patients Firstly, we examined the expression of Del1 protein in human colon cancer LS-174T and HT29 cells by immunohistochemical analysis as shown in Figure 1A (LS-174 cells) and 1B (HT29 cells)
The present study has demonstrated that downregulation of Del1 with small interfering RNA gene therapy targeting Del1 and vascular endothelial growth factor (VEGF) suppresses the growth of colon tumors by inhibiting angiogenesis and cell proliferation in vivo
Summary
Colon cancer is the fifth cause of cancer-related death in developed countries, and its incidence is rising at an alarming rate in developing countries [1]. The conventional adjuvant treatments have shown only modest effects on long-term survival after surgical resection. There is, an urgent need to seek novel therapies to treat colon cancer. Like all the other solid neoplasms, colon cancer depends on the process of angiogenesis, the formation of blood vessels, for both local and metastatic growth beyond a few cubic millimeters, which provides the rationale for antiangiogenic therapy aimed at targeting the tumor blood supply [2]. Inhibition of angiogenesis has become an attractive target for cancer therapy because it theoretically offers the hope of long-term control of neoplasm progression [3].
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