title: Lymphadenectomy promotes tumor growth and cancer cell dissemination in the spontaneous RET mouse model of human uveal melanoma.
abstract: Resection of infiltrated tumor-draining lymph nodes (TDLNs) is a standard practice for the treatment of several cancers including breast cancer and melanoma. However, many randomized prospective trials have failed to show convincing clinical benefits associated with LN removal and the role of TDLNs in cancer dissemination is poorly understood. Here, we found in a well-characterized spontaneous mouse model of uveal melanoma that the growth of the primary tumor was accompanied by increased lymphangiogenesis and cancer cell colonization in the LNs draining the eyes. But, unexpectedly, early resection of the TDLNs increased the growth of the primary tumor and associated blood vessels as well as promoted cancer cell survival and dissemination. These effects were accompanied by increased tumor cell proliferation and expression of phosphorylated AKT. Topical application of a broad anti-inflammatory agent, Tobradex, or an oral treatment with cyclooxygenase-2 specific inhibitor, Celecoxib, reversed tumor progression observed after complete lymphadenectomy. Our study confirms the importance of tumor homeostasis in cancer progression by showing the enhancing effects of TDLN removal on tumor growth and cancer cell dissemination, and suggests that TDLN resection may only be beneficial if used in combination with anti-inflammatory drugs such as Tobradex and Celecoxib.
authors.affiliation: Department of Microbiology, Immunology Programme, Life Science Institute, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yeo Kim
authors.initials: YK
authors.lastname: Pin
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.
authors.forename: Karen
authors.initials: K
authors.lastname: Khoo
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.
authors.forename: Muly
authors.initials: M
authors.lastname: Tham
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.|Department of Clinical Research, Singapore General Hospital, Singapore.
authors.forename: Tan
authors.initials: T
authors.lastname: Karwai
authors.affiliation: Department of Microbiology, Immunology Programme, Life Science Institute, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Thiam Chung
authors.initials: TC
authors.lastname: Hwee
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Puaux
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.
authors.forename: Meow Ling Cindy
authors.initials: ML
authors.lastname: Phua
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Microbiology, Immunology Programme, Life Science Institute, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Veronique
authors.initials: V
authors.lastname: Angeli
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.|Present address: Institut de Recherches Internationales Servier, Suresnes Cedex, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008197:Lymph Node Excision / Q000009:adverse effects*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary / Q000601:surgery*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D009389:Neovascularization, Pathologic; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013997:Time Factors; D047368:Tumor Burden; D014604:Uveal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D000098943:Uveal Melanoma
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D051057:Proto-Oncogene Proteins c-akt
keywords: inflammation; lymphadenectomy; uveal melanoma