Abstract
Tumor angiogenesis is essential for tumor invasive growth and metastasis, and generates abnormal vascular structures unlike developmental neovessel formation. To reduce tumor vascular abnormalities such as leakage and perivascular cell coverage deficiency that limit cancer therapy effectiveness, novel therapeutic approaches focus on vessel normalization. We have previously shown that Dickkopf-1 (DKK1), a Wnt antagonist, inhibits and its homolog DKK2 enhances, angiogenesis in normal tissues. In the present study, we investigated the effects of DKK1 and DKK2 on tumor growth and angiogenesis. Treatment of B16F10 melanoma-bearing mice with adenovirus expressing DKK1 significantly reduced tumor growth but DKK2 increased growth compared with controls. Similar pattern of tumor growth was observed in endothelial-specific DKK1 and DKK2 transgenic mice. Interestingly, tumor vascular density and perfusion were significantly decreased by DKK1 but increased by DKK2. Moreover, coverage of blood vessels by pericytes was reduced by DKK1, while DKK2 increased it. We further observed that DKK1 diminished retinal vessel density and increased avascular area in an in vivo murine model of oxygen-induced retinopathy, whereas DKK2 showed opposite results. These findings demonstrate that DKK1 and DKK2 have differential roles in normalization and functionality of tumor blood vessels, in addition to angiogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-013-9390-5) contains supplementary material, which is available to authorized users.
Highlights
Tumor angiogenesis is required for tumor development and supports rapid tumor growth [1]
We hypothesized that DKK1 and DKK2 effects on tumor growth may be due to altered tumor angiogenesis
This study examined the effects of DKK1 and DKK2, known Wnt antagonists, on B16F10 melanoma tumor proliferation and angiogenesis by using viral-mediated tumor transfectants and transgenic mice
Summary
Tumor angiogenesis is required for tumor development and supports rapid tumor growth [1]. Because tumor growth is robust, oxygen and nutrient supply by newly-formed vessels are often insufficient for optimal growth [2]. The hypoxic tumor environment induces secretion of growth factors including vascular endothelial growth factor (VEGF). Expressed growth factors disrupt normal angiogenic processes in tumors [3]. Tumor vessels show abnormal vascular features such as leakage, poor vascular coverage, and disorganized sprouting that inhibit vascular perfusion and increase tumor metastasis risk. Diverse angiogenic molecules are implicated in tumor angiogenesis, to date, VEGF has been the primary target in developing novel anti-angiogenic therapeutic
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