Division of Pediatric Oncology/Hematology, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Eur J Cancer. 2010 Mar;46(5):974-82. doi: 10.1016/j.ejca.2009.12.027. Epub 2010 Jan 22.
Increased levels of circulating VEGF-A have been demonstrated in patients with non-Hodgkin lymphoma (NHL) and are associated with progressive disease and poor clinical outcome. We investigated the role of VEGF-A in lymphoma tumour growth on a molecular level in order to identify the mechanism of VEGF-A-promoted tumour growth and to identify the potential targets for therapy. We used a model in which Daudi (human Burkitt lymphoma) tumour cells were transduced with VEGF-A165 or an empty vector (negative control) and subcutaneously injected in NOD/SCID mice. The weight of tumours overexpressing VEGF-A was increased 4-fold compared to that of control tumours (p<0.0001), whereas no in vitro growth advantage was demonstrated upon VEGF-A overexpression. VEGF-A-tumours were associated with increased microvessel densities (p=0.004) and increased tumour cell proliferation (Ki67; p<0.001) compared to control tumours. VEGF-A-tumours were characterised by upregulation of phosphorylated STAT-4 and STAT-6 and downregulation of phospho-p27(KIP1), a crucial cell cycle inhibitor (p<0.05). This was accompanied by increased levels of phosphorylated receptor tyrosine kinases, including EGFR (ErbB-2 and ErbB-4, p<0.05), an upstream regulator of STAT proteins. We demonstrated that various mouse-derived cytokines produced by mouse-derived tumour stromal cells are upregulated in VEGF-A-tumours compared to control tumours (p<0.05). These results indicate an important role for the tumour microenvironment in paracrine promotion of lymphoma tumour growth in response to tumour-derived VEGF-A. In conclusion, lymphoma-derived VEGF-A promoted lymphoma tumour growth in a paracrine loop by activation of tumour stromal cells. Our study reveals VEGF-A and STAT proteins as potential additional targets in the treatment of lymphoma.
在非霍奇金淋巴瘤 (NHL) 患者中已经证实循环 VEGF-A 水平升高，并且与进行性疾病和不良临床结局相关。我们在分子水平上研究了 VEGF-A 在淋巴瘤肿瘤生长中的作用，以确定 VEGF-A 促进肿瘤生长的机制，并确定潜在的治疗靶点。我们使用了一种模型，其中将 Daudi（人伯基特淋巴瘤）肿瘤细胞转导 VEGF-A165 或空载体（阴性对照），并皮下注射到 NOD/SCID 小鼠中。与对照肿瘤相比，过表达 VEGF-A 的肿瘤重量增加了 4 倍（p<0.0001），而在过表达 VEGF-A 时并未表现出体外生长优势。与对照肿瘤相比，VEGF-A 肿瘤与微血管密度增加（p=0.004）和肿瘤细胞增殖增加（Ki67；p<0.001）相关。与对照肿瘤相比，VEGF-A 肿瘤的特征是磷酸化 STAT-4 和 STAT-6 上调以及细胞周期抑制剂磷酸化 p27(KIP1)下调（p<0.05）。这伴随着包括 EGFR（ErbB-2 和 ErbB-4）在内的磷酸化受体酪氨酸激酶水平的增加，这些激酶是 STAT 蛋白的上游调节剂（p<0.05）。我们证明与对照肿瘤相比，VEGF-A 肿瘤中各种由小鼠衍生的肿瘤基质细胞产生的细胞因子水平上调（p<0.05）。这些结果表明肿瘤微环境在肿瘤衍生的 VEGF-A 刺激的淋巴瘤肿瘤生长的旁分泌促进中起重要作用。总之，淋巴瘤衍生的 VEGF-A 通过激活肿瘤基质细胞在旁分泌环中促进淋巴瘤肿瘤生长。我们的研究揭示了 VEGF-A 和 STAT 蛋白作为淋巴瘤治疗的潜在额外靶点。
