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.