Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-752, Republic of Korea.
Angiogenesis. 2014 Jan;17(1):221-34. doi: 10.1007/s10456-013-9390-5. Epub 2013 Oct 4.
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.
肿瘤血管生成对于肿瘤的侵袭性生长和转移至关重要，它会产生不同于发育性新血管形成的异常血管结构。为了减少肿瘤血管的异常，如渗漏和血管周围细胞覆盖不足，这些异常会限制癌症治疗的效果，新的治疗方法侧重于血管正常化。我们之前已经表明，Wnt 拮抗剂 Dickkopf-1（DKK1）抑制正常组织中的血管生成，而其同源物 DKK2 则增强血管生成。在本研究中，我们研究了 DKK1 和 DKK2 对肿瘤生长和血管生成的影响。用表达 DKK1 的腺病毒处理 B16F10 黑色素瘤荷瘤小鼠，可显著抑制肿瘤生长，但与对照组相比，DKK2 增加了肿瘤生长。内皮特异性 DKK1 和 DKK2 转基因小鼠也观察到了类似的肿瘤生长模式。有趣的是，DKK1 显著降低了肿瘤血管密度和灌注，而 DKK2 则增加了。此外，DKK1 减少了周细胞对血管的覆盖，而 DKK2 则增加了。我们进一步观察到，DKK1 减少了在氧诱导的视网膜病变的体内小鼠模型中的视网膜血管密度，并增加了无血管区域，而 DKK2 则表现出相反的结果。这些发现表明，DKK1 和 DKK2 在肿瘤血管的正常化和功能方面具有不同的作用，除了血管生成。
