Cellular and molecular mechanisms of tumor-induced lymphangiogenesis

自从描述了特定的淋巴管标志物以来，淋巴管生成在癌症研究中的作用越来越大。我们将研究肿瘤与淋巴管内皮细胞的相互作用是否诱导淋巴管内皮细胞中特定的新基因。所使用的系统将是小鼠胚胎干细胞来源的类胚体分析和新建立的肿瘤转移模型。以前，针对淋巴管生成和血管生成的靶向研究几乎都是在原发肿瘤模型中进行的。然而，在人类患者中，原发肿瘤通常是切除的，转移瘤的治疗是最具挑战性的治疗问题。为了更好地模拟人类的情况，我们必须针对原发肿瘤切除后的淋巴转移。在我们观察到的乳腺癌模型中，与对照肿瘤相比，表达VEGF-C的MDA肿瘤的前哨淋巴结中淋巴管生成增加，类似于在转基因小鼠的皮肤癌模型和人类黑色素瘤转移中观察到的变化1，2我们将评估肿瘤相关淋巴管内皮细胞中基因的上调以及阻断抗体对肿瘤从前哨淋巴结进一步扩散的影响。此外，我们将评估这些抗体对前哨和远处淋巴结内淋巴流动的影响。这两个系统(体内/体外)将使我们能够定义新的特定靶点，以及阻断淋巴结淋巴管生成对肿瘤扩散的影响。

Since the description of specific lymphatics markers the role of lymphangiogenesis in cancer research is increasing. We will investigate whether tumor-lymphendothelial interaction induces specific new genes in lymphatic endothelial cells. The used systems will be a murine embryonic stem cell derived embryoid body assay and a new established tumor metastasis model. Previously, the targeting of lymphangiogenesis and angiogenesis was almost exclusively studied in primary tumor models. However, in human patients primary tumors are usually excised and the treatment of metastases represents the most challenging therapeutic problem. To better mimic the human situation, we have to target the lymph node metastasis after the removal of the primary tumor. In a breast carcinoma model we observed, that lymphangiogenesis is increased in the sentinel lymph nodes of VEGF-C expressing MDA tumors compared to control tumors, similar to changes observed in a skin carcinoma model in VEGF-Atransgenic mice and in human melanoma metastasis.1, 2 We will evaluate the upregulation of genes in the tumor associated lymphatic endothelial cells and the influence of blocking antibodies on further cancer spread from the sentinel lymph node. Moreover we will evaluate the impact of these antibodies on the lymph flow inside sentinel and distant lymph nodes. These two systems (in vivo / in vitro) will allow us to define new specific targets and the impact of blocking lymph node lymphangiogenesis on tumor spread.