title: Genetic Identification of SEMA3F as an Antilymphangiogenic Metastasis Suppressor Gene in Head and Neck Squamous Carcinoma.
abstract: Head and neck squamous cell carcinomas (HNSCC) often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. HNSCCs are remarkably lymphangiogenic and represent a clear example of a cancer that utilizes the lymphatic vasculature for malignant dissemination; however, the molecular mechanisms underlying lymphangiogenesis in HNSCC is still poorly understood. Of interest, we found that an axon guidance molecule, Semaphorin 3F (SEMA3F), is among the top 1% underexpressed genes in HNSCC, and that genomic loss of SEMA3F correlates with increased metastasis and decreased survival. SEMA3F acts on its coreceptors, plexins and neuropilins, among which neuropilin-2 (NRP2) is highly expressed in lymphatic endothelial cells (LEC) but not in oral epithelium and most HNSCCs. We show that recombinant SEMA3F promotes LEC collapse and potently inhibits lymphangiogenesis in vivo. By reconstituting all possible plexin and neuropilin combinations, we found that SEMA3F acts through multiple receptors, but predominantly requires NRP2 to signal in LECs. Using orthotopic HNSCC metastasis mouse models, we provide direct evidence that SEMA3F re-expression diminishes lymphangiogenesis and lymph node metastasis. Furthermore, analysis of a large tissue collection revealed that SEMA3F is progressively lost during HNSCC progression, concomitant with increased tumor lymphangiogenesis. SEMA3F is localized to 3p21, an early and frequently deleted locus in HNSCC and many other prevalent human malignancies. Thus, SEMA3F may represent an antilymphangiogenic metastasis suppressor gene widely lost during cancer progression, hence serving as a prognostic biomarker and an attractive target for therapeutic intervention to halt metastasis.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Doçi
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Mikelis
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland. sg39v@nih.gov.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D019556:COS Cells; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491230:SEMA3F protein, human