Dickkopf‐1 expression is down‐regulated during the colorectal adenoma–carcinoma sequence and correlates with reduced microvessel density and VEGF expression

AIMS: Dickkopf-1 (Dkk1), an antagonist of the Wnt-β-catenin signalling pathway, has been reported to play a role in cancer progression. However, little is known about the role of Dkk1 during the colorectal adenoma-carcinoma sequence. This study aimed to elucidate the role of Dkk1 in tumorigenesis and angiogenesis in colorectal cancer. METHODS AND RESULTS: We examined Dkk1 expression immunohistochemically in 476 colorectal tissue samples, including 46 sets of matched specimens. Dkk1 expression was down-regulated during the colorectal adenoma-carcinoma sequence, both among the 476 samples and in the 46 sets of matched specimens. Dkk1 expression was correlated with decreased microvessel density (P < 0.05) and VEGF expression. In-vitro 3D coculture experiments showed that Dkk1 overexpression in HCT116 cells inhibited tube-like structure formation and down-regulated VEGF expression in human umbilical vein endothelial cells. Xenografts of Dkk1-overexpressing colorectal cancer cells were smaller, and showed lower microvessel density and VEGF expression levels, than those of control cells. CONCLUSIONS: This study is the first to show the roles of Dkk1 during the colorectal adenoma-carcinoma sequence, which may involve suppression of the tumorigenesis and angiogenesis of CRC. Dkk1 could therefore serve as a potential target for tumour therapy.