Schoeffner Daniel J, Matheny Shannon L, Akahane Takemi, Factor Valentina, Berry Adam, Merlino Glenn, Thorgeirsson Unnur P
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Lab Invest. 2005 May;85(5):608-23. doi: 10.1038/labinvest.3700258.
Vascular endothelial growth factor (VEGF) has been identified as a vascular permeability factor, angiogenic cytokine, and a survival factor. To address its role in mammary carcinogenesis, we used transgenic mice with human VEGF(165) targeted to mammary epithelial cells under the control of the mouse mammary tumor virus (MMTV) promoter. Metastatic mammary carcinomas were induced by mating the MMTV-VEGF mice with MMTV-polyoma virus middle T-antigen (MT) mice to generate VEGF/MT mice. Tumor latency was decreased in the VEGF/MT mice, which developed mammary carcinomas with increased vasodilatation at 4 weeks of age. There was increased incidence, multiplicity, and weight of the mammary tumors in 6- and 8-week-old VEGF/MT mice, compared to their MT-only littermates. Macro- and microscopic lung metastases were detected in the VEGF/MT mice but not the MT mice at 6 and 8 weeks of age. Enhanced tumor growth was attributed to increased microvascular density (MVD), as well as increased tumor cell proliferation and survival. Angiogenesis array analysis showed that 24 of 25 differentially expressed genes were upregulated in the VEGF/MT tumors. In vitro studies revealed increased proliferative activity and upregulation of Flk-1 in the VEGF/MT tumor cells, compared with the MT-only tumor cells. Moreover, there was decreased proliferative activity with downregulation of Flk-1 in tumor cells isolated from conditional knockout (VEGF(-/-)) MT-induced mammary carcinomas. The slow growing VEGF(-/-) tumor cells were accumulated in the G(1)/G(0) phase of the cell cycle and this was associated with stimulation of p16(ink4a) and p21(WAF1). Similarly, p16(ink4a) was stimulated in VEGF(lox/lox)/MT mammary tumor cells following Adeno-cre-mediated VEGF gene inactivation. Collectively, the data from these transgenic models indicate that VEGF contributes to mammary tumor growth through increased neovascularization, as well as autocrine stimulation of growth and inhibition of apoptosis.
血管内皮生长因子（VEGF）已被确认为一种血管通透性因子、血管生成细胞因子和生存因子。为了研究其在乳腺癌发生中的作用，我们使用了转基因小鼠，其在小鼠乳腺肿瘤病毒（MMTV）启动子的控制下，将人VEGF(165)靶向乳腺上皮细胞。通过将MMTV-VEGF小鼠与MMTV-多瘤病毒中T抗原（MT）小鼠交配，诱导转移性乳腺癌，以产生VEGF/MT小鼠。VEGF/MT小鼠的肿瘤潜伏期缩短，在4周龄时就发展出血管扩张增加的乳腺癌。与仅MT的同窝小鼠相比，6周龄和8周龄的VEGF/MT小鼠乳腺肿瘤的发生率、多发性和重量均增加。在6周龄和8周龄时，在VEGF/MT小鼠中检测到宏观和微观的肺转移，而MT小鼠中未检测到。肿瘤生长增强归因于微血管密度（MVD）增加，以及肿瘤细胞增殖和存活增加。血管生成阵列分析表明，25个差异表达基因中的24个在VEGF/MT肿瘤中上调。体外研究显示，与仅MT的肿瘤细胞相比，VEGF/MT肿瘤细胞的增殖活性增加，Flk-1上调。此外，从条件性敲除（VEGF(-/-)）MT诱导的乳腺癌中分离的肿瘤细胞中，Flk-1下调，增殖活性降低。生长缓慢的VEGF(-/-)肿瘤细胞积聚在细胞周期的G(1)/G(0)期，这与p16(ink4a)和p21(WAF1)的刺激有关。同样，在腺病毒介导的VEGF基因失活后，VEGF(lox/lox)/MT乳腺肿瘤细胞中p16(ink4a)受到刺激。总的来说，这些转基因模型的数据表明，VEGF通过增加新生血管形成以及自分泌生长刺激和细胞凋亡抑制，促进乳腺肿瘤生长。
