Chen W, Li F, Mead L, White H, Walker J, Ingram D A, Roman A
Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120, USA.
Virology. 2007 Oct 10;367(1):168-74. doi: 10.1016/j.virol.2007.05.030. Epub 2007 Jun 28.
One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.
肿瘤生长的必要条件之一是具备募集血液供应的能力，这一过程称为血管生成。血管生成在宫颈疾病从轻度发育异常进展至重度发育异常再到浸润性癌的早期阶段就已开始。我们之前报道过，人乳头瘤病毒16型E6和E7（HPV16 E6E7）蛋白在原代包皮角质形成细胞（HFK）中的表达会降低两种抑制剂的表达，并增加两种血管生成诱导剂的表达[图森特 - 史密斯，E.，唐纳，D.B.，罗曼，A.，2004年。人乳头瘤病毒16型E6和E7癌蛋白在原代包皮角质形成细胞中的表达足以改变血管生成因子的表达。《癌基因》23卷，第2988 - 2995页]。在此我们报告，HPV诱导的角质形成细胞表型早期变化足以在体外和体内改变内皮细胞行为。来自表达HPV16 E6E7的HFK以及含有完整HPV16的人宫颈角质形成细胞的条件培养基能够刺激人微血管内皮细胞的增殖和迁移。此外，使用基质胶栓模型将条件培养基引入具有免疫活性的小鼠体内会引发明显的血管生成反应。这些新数据支持了这样一种假说，即HPV蛋白不仅促成了HPV感染后出现的角质形成细胞不受控制的生长，还促成了肿瘤形成所需的血管生成反应。
