Dilated lymphatic vessels with cancer cell invasion, apoptosis, and cell proliferation in mammary carcinomas. Podoplanin-positive lymphatic microvessels of a tumor in a control mouse were often dilated and filled with tumor cells (A). The pesVEGFR-2 (B) and pEndo (C) groups showed a reduction in the numbers of dilated lymphatic microvessels containing intralumenal tumor cells (A-C, scale bar = 50 μm). Whereas some TUNEL-positive cells are seen in the tumor of a control mouse (D) and a mouse treated with pesVEGFR-2 (E), many more TUNEL-positive cells are observed in the tumor of a mouse treated with pEndo (F) (D-F, scale bar = 50 μm). Higher magnification in F showed many TUNEL-positive cells are observed in along with brownish necrotic vessels (G, arrows) (scale bar = 25 μm). Apoptosis of the tumor cells may be due to injury of the blood vessels (blockage of oxygen supply and nutrition to tumor cells). The number of BrdU-labeled cells tended to be lower in the pesVEGFR-2 (I) and pEndo (J) groups than in the pVec group (H) (H-J, scale bar = 50 μm). A-C, podoplanin immunohistochemistry; D-G, TUNEL stain; H-J, BrdU immunohistochemistry.