title: Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis.
abstract: Tumor lymphangiogenesis is now known to play a causal role in lymph node metastasis, and thus its inhibition would have great significance for the prevention of lymph node metastasis in cancer therapy. VEGF-C has recently been identified as a key molecule that involved in tumor lymphangiogenesis and lymphatic metastasis. However, the expressional regulation of VEGF-C is not fully understood. We investigated the role of mTOR, which is a downstream kinase of the phosphatidylinositol 3-kinase/Akt pathway, and the MAPK family (MEK1/2, p38, and JNK) in the regulation of VEGF-C and VEGF-A expression in B13LM cells, a lymphatic metastasis-prone pancreatic tumor cell line. We also investigated the antilymphangiogenic effect of rapamycin, a specific inhibitor of mTOR in vivo using male BALB/c nu/nu mice. VEGF-C expression was inhibited by the inhibitors for mTOR, p38, and JNK, but not by the inhibitor for MEK1/2, whereas VEGF-A expression was inhibited by all four of these inhibitors. The serum starvation-induced expression of VEGF-C was inhibited by rapamycin, whereas that of VEGF-A was incompletely inhibited. The metastatic experiment in vivo demonstrated that the number and the area of lymphatic vessels in the primary tumors were significantly decreased by rapamycin. Finally, the lymph node metastasis was significantly suppressed in rapamycin-treated mice. Our results suggest that mTOR, p38, and JNK play important roles in VEGF-C expression, and that rapamycin has an antilymphangiogentic effect and exerts the expected inhibition of lymphatic metastasis.
authors.affiliation: Departments of Molecular Pathology, and General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kamata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishikura
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D042583:Lymphangiogenesis / Q000187:drug effects*; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus