Costa Maria José, Wu Xiaoqing, Cuervo Henar, Srinivasan Ruchika, Bechis Seth K, Cheang Ellen, Marjanovic Olivera, Gridley Thomas, Cvetic Christin A, Wang Rong A
Laboratory for Accelerated Vascular Research, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, CA 94143, USA.
Present address: Department of Pediatrics and Program in Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
Vasc Cell. 2013 Apr 20;5(1):7. doi: 10.1186/2045-824X-5-7.
Notch4 is a member of the Notch family of receptors that is primarily expressed in the vascular endothelial cells. Genetic deletion of Notch4 does not result in an overt phenotype in mice, thus the function of Notch4 remains poorly understood.
We examined the requirement for Notch4 in the development of breast cancer vasculature. Orthotopic transplantation of mouse mammary tumor cells wild type for Notch4 into Notch4 deficient hosts enabled us to delineate the contribution of host Notch4 independent of its function in the tumor cell compartment.
Here, we show that Notch4 expression is required for tumor onset and early tumor perfusion in a mouse model of breast cancer. We found that Notch4 expression is upregulated in mouse and human mammary tumor vasculature. Moreover, host Notch4 deficiency delayed the onset of MMTV-PyMT tumors, wild type for Notch4, after transplantation. Vessel perfusion was decreased in tumors established in Notch4-deficient hosts. Unlike in inhibition of Notch1 or Dll4, vessel density and branching in tumors developed in Notch4-deficient mice were unchanged. However, final tumor size was similar between tumors grown in wild type and Notch4 null hosts.
Our results suggest a novel role for Notch4 in the establishment of tumor colonies and vessel perfusion of transplanted mammary tumors.
Notch4是Notch受体家族的成员之一，主要在血管内皮细胞中表达。Notch4基因敲除在小鼠中并未导致明显的表型，因此Notch4的功能仍知之甚少。
我们研究了Notch4在乳腺癌血管生成中的作用。将Notch4野生型的小鼠乳腺肿瘤细胞原位移植到Notch4缺陷型宿主中，使我们能够明确宿主Notch4的作用，而不依赖于其在肿瘤细胞中的功能。
在此，我们表明在乳腺癌小鼠模型中，Notch4的表达对于肿瘤发生和早期肿瘤灌注是必需的。我们发现Notch4在小鼠和人类乳腺肿瘤血管中的表达上调。此外，宿主Notch4缺陷会延迟移植后Notch4野生型的MMTV-PyMT肿瘤的发生。Notch4缺陷型宿主中形成的肿瘤的血管灌注减少。与抑制Notch1或Dll4不同，Notch4缺陷型小鼠中形成的肿瘤的血管密度和分支没有变化。然而，野生型和Notch4基因敲除型宿主中生长的肿瘤最终大小相似。
我们的结果表明Notch4在移植乳腺肿瘤的肿瘤集落形成和血管灌注中具有新作用。
