Dual Expression of Neuropilin‐2 in Tumor and Stroma in Oral Dysplasia and Oral Squamous Cell Carcinoma

Abstract

The majority of oral malignancies (90%) are squamous cell carcinoma (OSCC), and two‐thirds of OSCC patients present at diagnosis with disseminated disease. OSCC can develop from pre‐cancerous lesions known as oral dysplasia. Early detection of these lesions leads to better management and outcome. We investigated the role of the Neuropilin‐2 (NRP2) cell surface receptor in oral dysplasia and OSCC. NRP2 is regarded as an important mediator of angiogenesis and lymphangiogenesis, but its role in epithelial cells is less understood. NRP2 can bind VEGFA in a complex with VEGFR2 or VEGFC in a complex with VEGFR3 to stimulate the sprouting of blood or lymphatic vessels during development but its role in adult tumor‐associated neovascularization has not been clearly identified. Interestingly, NRP2 also binds Semaphorin‐3F (SEMA3F) in a competitive fashion with VEGFA/C, and SEMA3F is reported to inhibit lymphangiogenesis. Here, we hypothesize that oral dysplasia and OSCC express NRP2 in transformed epithelial cells as well as in tumor‐associated lymphatic endothelium, and that this expression pattern renders them amenable to SEMA3F therapy. Our results indicate that adult human and mice normal tongue do not express NRP2 in the epithelium or in quiescent lymphatic vessels. However, NRP2 is significantly upregulated in moderate or severe oral dysplasia and OSCC in epithelial cells and lesion‐associated lymphatic vessels. Two different human OSCC cell lines injected orthotopically in immunocompromised mice showed high NRP2 expression. Immunocytostaining also confirmed NRP2 protein expression in two different cell lines isolated from 4NQO‐induced OSCC in mice. Additionally, a panel of different human and mice OSCC cell lines showed high expression of NRP2 protein using western blot. Lastly, SEMA3F, in a dose‐dependent manner, inhibited migration of Nrp2‐expressing mouse OSCC cells in vitro. In summary, the upregulation of NRP2 in early stages of cancer progression in OSCC may point to important signaling pathways not previously realized in disease. Targeting NRP2 with neutralizing antibodies or with its inhibitory SEMA3F ligand may a promising new paradigm to treat or prevent progression and metastasis of OSCC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.