**3.4.1 Lymphangiogenesis in cholangiocarcinoma**

The role of lymphangiogenesis in cholangiocarcinoma metastasis and progression is largely unknown and controversial. However, recent studies suggest that there is a correlation between lymphangiogenesis and lymph node metastases and prognosis; patients diagnosed with cholangiocarcinoma tumors exhibiting low lymphatic vessel density have a longer survival rate than those with higher lymphatic vessel density (Thelen et al. 2008). In addition, in intrahepatic cholangiocarcinoma tumors, high lymphatic vessel density correlated with increased nodal spread and higher recurrence rate (Thelen et al. 2009). Conversely, other researchers demonstrated that in intrahepatic cholangiocarcinoma tumors, lymph node metastasis did not correlate with lymphangiogenesis, but did correlate with VEGF-C expression and the presence of a subset of myofibroblasts expressing the same markers as lymphendothelial cells (Aishima et al. 2008), which may explain the discrepancy in conclusions.

NGF has previously been linked to tumor progression and growth (Sortino et al. 2000; Descamps et al. 2001a; Descamps et al. 2001b) as well as VEGF expression (Lazarovici et al. 2006a; Lazarovici et al. 2006b) in a number of other cell types. Therefore, Xu et al. assessed the correlation of NGF- expression with lymphangiogenesis, lymph node metastasis or VEGF-C expression in hilar cholangiocarcinoma tissue (Xu et al. 2010). Indeed, high NGF expression was correlated with VEGF-C overexpression, lymphatic vessel density, and lymph node metastasis suggesting that NGF may also be responsible for stimulating lymphangiogenesis in cholangiocarcinoma tumors.
