title: Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse.
abstract: In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria. dontscho.kerjaschki@meduniwien.ac.at
authors.forename: Dontscho
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authors.lastname: Kerjaschki
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authors.forename: Sandra
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authors.lastname: Madlener
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authors.forename: Agnes
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authors.lastname: Davidovits
authors.forename: Hitonari
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authors.lastname: Nosaka
authors.forename: Monika
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authors.lastname: Hämmerle
authors.forename: Katharina
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authors.lastname: Viola
authors.forename: Helmut
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authors.lastname: Dolznig
authors.forename: Martin
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authors.lastname: Schreiber
authors.forename: Alexander
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authors.lastname: Nader
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authors.lastname: Hirakawa
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authors.lastname: Detmar
authors.forename: Kari
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authors.lastname: Alitalo
authors.forename: Sebastian
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authors.lastname: Nijman
authors.forename: Felix
authors.initials: F
authors.lastname: Offner
authors.forename: Thorsten J
authors.initials: TJ
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mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000737:chemistry; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism*; D008207:Lymphatic Metastasis; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D009097:Multienzyme Complexes; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D008084:Lipoxygenase; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase