LEKTI, A Physiological Inhibitor of Multiple Serine Proteinases, Suppresses Perineural and Lymphovascular Invasion of Human Head and Neck Cancer Cells in A Mouse Orthotopic Model

Abstract

Serine Protease Inhibitor Kazal-type 5 (SPINK5) gene encodes 3 different LymphoEpithelial Kazal-Type-Inhibitor (LEKTI) isoforms. We identified and cloned LEKTI by its constitutive expression in normal oral mucosa and its loss of expression in matched tumor specimens of patients with head and neck squamous cell carcinoma (HNSCC). Stable re-expression of LEKTI in HNSCC OSC19 cells resulted in reduced migration and invasionand enhanced adhesion on variety of ECM substrates in vitrowith a concomitant reduction inexpression of endogenous MMP-14, MMP-8, KLK5, and ADAM8. Here, we sought to determine the consequences of LEKTI re-expression on the in vivo changes in the tumor growth and invasion using an orthotopic model of tongue cancer. In the tongue tumors of mice, lymphovascular invasion or perineural spread was found in 100% of tumors derived from parental cell lines but was almost totally absent in all tumors derived from LEKTI-expressing clones. Our work suggests that loss of LEKTI expression in primary tumors might correlate with aggressive biologic behavior and restoration of LEKTI expression by pharmacologic means might be beneficial for patients with HNSCC.