Von Marschall Zofia, Scholz Arne, Stacker Steven A, Achen Marc G, Jackson David G, Alves Frauke, Schirner Michael, Haberey Martin, Thierauch Karl-Heinz, Wiedenmann Bertram, Rosewicz Stefan
Department of Hepatology, Gastroenterology, Endocrinology and Metabolism, Charité-University Medicine Berlin, CVK, D-13353 Berlin, Germany.
Int J Oncol. 2005 Sep;27(3):669-79.
The presence of lymphatic metastases is a strong indicator for poor prognosis in patients with ductal pancreatic cancer. In order to better understand the mechanisms controlling lymphatic growth and lymph node metastasis in human ductal pancreatic cancer, we analyzed the expression pattern of the vascular endothelial growth factor-D (VEGF-D), its receptor VEGF-receptor-3 (VEGFR-3) and the lymphatic endothelium-specific hyaluronan receptor LYVE-1 in a panel of 19 primary human ductal pancreatic tumors and 10 normal pancreas specimens. We further addressed the biological function of VEGF-D for induction of lymphatic metastasis in a nude mouse xenograft model using two human ductal pancreatic cancer cell lines with overexpression of VEGF-D. Compared to normal human pancreas, pancreatic cancer tissue showed overexpression of VEGF-D and VEGFR-3 in conjunction with a high lymphatic vascularization as determined by immunohistochemistry and in situ hybridization. Tumors derived from VEGF-D-overexpressing cells had a higher microvessel density compared to their mock-controls, as determined based on CD31 immunohistochemistry. Importantly, these tumors also revealed a significant induction of intra- and peritumoral lymphatics, as judged from immunohistochemical detection of LYVE-1 expression. This was associated with a significant increase in lymphatic vessel invasion by tumor cells and an increased rate of lymphatic metastases, as indicated by pan-cytokeratin reactive cells in lymph nodes. Our results suggest that VEGF-D plays a pivotal role in stimulating lymphangiogenesis and lymphatic metastasis in human ductal pancreatic cancer, and therefore represents a novel therapeutic target for this devastating disease.
淋巴转移的存在是导管胰腺癌患者预后不良的有力指标。为了更好地了解控制人类导管胰腺癌中淋巴管生长和淋巴结转移的机制，我们分析了19例原发性人类导管胰腺肿瘤和10例正常胰腺标本中血管内皮生长因子-D（VEGF-D）、其受体VEGF受体-3（VEGFR-3）以及淋巴管内皮特异性透明质酸受体LYVE-1的表达模式。我们还使用两种过表达VEGF-D的人类导管胰腺癌细胞系，在裸鼠异种移植模型中进一步探讨了VEGF-D诱导淋巴转移的生物学功能。与正常人类胰腺相比，通过免疫组织化学和原位杂交确定，胰腺癌组织显示VEGF-D和VEGFR-3过表达，同时伴有高淋巴管生成。根据CD31免疫组织化学检测，与对照相比，源自过表达VEGF-D细胞的肿瘤具有更高的微血管密度。重要的是，根据LYVE-1表达的免疫组织化学检测判断，这些肿瘤还显示肿瘤内和肿瘤周围淋巴管明显增多。这与肿瘤细胞淋巴管侵犯显著增加以及淋巴结中全细胞角蛋白反应性细胞所表明的淋巴转移率增加相关。我们的结果表明，VEGF-D在刺激人类导管胰腺癌的淋巴管生成和淋巴转移中起关键作用，因此代表了这种毁灭性疾病的一个新的治疗靶点。
