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The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.

ABSTRACT: Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report that Dickkopf1 (DKK1) and Dickkopf2 (DKK2), originally known as WNT antagonists, play opposite functional roles in regulating angiogenesis. DKK2 induced during EC morphogenesis promoted angiogenesis in cultured human endothelial cells and in in vivo assays using mice. Its structural homolog, DKK1, suppressed angiogenesis and was repressed upon induction of morphogenesis. Importantly, local injection of DKK2 protein significantly improved tissue repair, with enhanced neovascularization in animal models of both hind limb ischemia and myocardial infarction. We further showed that DKK2 stimulated filopodial dynamics and angiogenic sprouting of ECs via a signaling cascade involving LRP6-mediated APC/Asef2/Cdc42 activation. Thus, our findings demonstrate the distinct functions of DKK1 and DKK2 in controlling angiogenesis and suggest that DKK2 may be a viable therapeutic target in the treatment of ischemic vascular diseases.

SUBMITTER: Min JK

PROVIDER: S-EPMC3083777 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.

Min Jeong-Ki JK Park Hongryeol H Choi Hyun-Jung HJ Kim Yonghak Y Pyun Bo-Jeong BJ Agrawal Vijayendra V Song Byeong-Wook BW Jeon Jongwook J Maeng Yong-Sun YS Rho Seung-Sik SS Shim Sungbo S Chai Jin-Ho JH Koo Bon-Kyoung BK Hong Hyo Jeong HJ Yun Chae-Ok CO Choi Chulhee C Kim Young-Myoung YM Hwang Ki-Chul KC Kwon Young-Guen YG

The Journal of clinical investigation 20110411 5

Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report t ...[more]

PMID: 21540552

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Project description:Angiogenesis is a fundamental process that involves in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) family and their receptors are identified as the most prominent regulators of angiogenesis. However, the clinical efficacy of anti-VEGF/VEGFR therapy is not ideal, prompting the needs to further understand mechanisms behind tumor angiogenesis. Here, we found that Dickkopf associated protein 2 (DKK2), a secretory protein highly expressed in metastatic colorectal cancer tissues, could stimulate angiogenesis via a classic VEGF/VEGFR independent pathway. Methods: DKK2 was screened out from microarray data analyzing gene expression profiles of eight pairs of non-metastatic and metastatic human colorectal cancer (CRC) tissues. Immunofluorescence histochemical staining (IHC) was used to detect the expression of DKK2 and angiogenesis in CRC tissues. Chicken chorioallantoic membrane (CAM) assay and Human umbilical vein endothelial cells (HUVEC) tubule formation assay was used for in vitro and in vivo angiogenesis study, respectively. Lactate and glucose concentration in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter assay was used to verify the interaction between miR-493-5p and the 3'UTR of DKK2. Results: DKK2 could stimulate angiogenesis via accelerating the aerobic glycolysis of CRC cells, through which lactate is produced from glucose and accumulated in tumor microenvironment. Lactate functions as the final executor of DDK2 to stimulate tube formation of endothelial cells, and blockage of lactate secretion by lactate transporter (MCT) inhibitors dramatically neutralize the progression and metastasis of CRC both in vitro and in vivo. DKK2 could cooperate with lipoprotein receptor-related protein 6, which is required for glucose uptake, and activated the downstream mTOR signal pathway to accelerate lactate secretion. In addition, the expression of DKK2 is switched on via the demethylation of miR-493-5p, which allows the dissociated of miR-493-5p from the 3'-UTRs of DKK2 and initiates its stimulatory role on CRC progression in an autocrine or paracrine manner. Conclusion: DKK2 promotes tumor metastasis and angiogenesis through a novel VEGF-independent, but energy metabolism related pathway. DKK2 might be a potential anti-angiogenic target in clinical treatment for the advanced CRC patients.

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The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.

Publications

The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.

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