Figure 2. Steps of lymphatic metastasis and the effect of anti-lymphangiogenic treatment.
Elevated tumor IFP increases interstitial fluid flow at the tumor margin (Jain et al., 2007). The exudates, which contain fluid, protein, and cells from tumors, are collected in the peritumoral lymphatic vessels. Although the mechanical signals that could trigger the lymphangiogenic switch are not known, hydrostatic pressure is likely to be such trigger (Boardman and Swartz, 2003). Furthermore, many tumors express lymphangiogenic factors such as VEGF-C (Alitalo et al., 2005). (A) FITC-dextran microlymphangiography of peritumor and normal lymphatics in mouse ears. Bar, 850 μm. MT, mock transduced. VEGF-C, VEGF-C overexpressing. Lymphatic vessels are hyperplastic in the peritumor region and ear base (further down stream) of the T241 fibrosarcomas. VEGF-C expression further increases lymphatic vessel diameter. Number of lymphatic vessels is also increased in the tumor periphery especially in the presence of excess VEGF-C (Isaka et al., 2004). Malformed lymphatic valves allow retrograde flow in these lymphatic vessels and facilitate transfer of metastasizing tumor cells, which can be visualized by intravital microscopy after the transfection of GFP expression vector (Hoshida et al., 2006). (B) Then GFP-positive tumor cells (green) are observed entering the cervical lymph node from afferent lymphatic (red, arrow) by MPLSM. Bar, 100 μm. VEGF-C overexpression significantly increases arrival of tumor cells to the lymph node. Macroscopic lymph node metastasis increases with the increase of tumor cell arrival to the lymph node (Hoshida et al., 2006). (C) The treatment with anti-VEGF receptor 3 antibody (mF4-31C1) significantly reduces peritumor and ear base lymphatic vessel size. (D) Tumor cells cannot reach to the cervical lymph node under the anti-VEGFR3 treatment. As a result, macroscopic lymph node is significantly reduced by anti-VEGFR3 treatment if it is given before the arrival of tumor cells to the lymph node (Hoshida et al., 2006). A–C, adapted or reproduced from (Hoshida et al., 2006).