The potential of Tenascin C in the tumor-nerve microenvironment to enhance perineural invasion and correlate with locoregional recurrence-related poor prognosis in pancreatic ductal adenocarcinoma.

748 Background: Perineural invasion (PNI) is commonly seen in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. However, the detail mechanisms of PNI in PDAC remain unclear. Tenascin C (TNC), an extracellular matrix glycoprotein, is abundant in cancer stroma and modulates tumor progression. In this study, we hypothesized that TNC could enhance PNI in PDAC. The aim of this study was to investigate the roles of TNC in the tumor-nerve microenvironment of PDAC. Methods: We immunohistochemically examined TNC expression in 78 resected PDAC specimens. TNC staining intensity in perineural sites at the invasive front was classified as low or high, by comparison with adjacent non-cancerous tissues in the same section. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Furthermore, interactions between cancer cells and nerves after supplementation with TNC were investigated using in vitro co-culture model with a PDAC cell line and neonatal mouse dorsal root ganglion (DRG). Results: High perineural TNC expression at the invasive front, seen in 30 (38%) patients, was associated with the presence of PNI (p = 0.006), pathological T stage ≥ 3 (p = 0.01), and postoperative locoregional recurrence (p = 0.002). It was independently associated with postoperative, poor recurrence-free survival in multivariate analysis (p = 0.045). In the in vitro co-culture model, TNC supplementation significantly enhanced both neurotropism of PDAC cells and tumor tropism of a DRG. On the other hand, when PDAC cells and a DRG were cultured separately, TNC did not affect cancer cell proliferation or neural outgrowth. Furthermore, the knockdown of Annexin A2, which is known to be a receptor for TNC, cancelled the neurotropism of PDAC cell toward DRGs. Conclusions: Strong perineural TNC expression was a prognostic indicator of locoregional recurrence-related poor prognosis. The neurotropism of PDAC induced by TNC and TNC-Annexin A2 signaling pathway could be the potential therapeutic target for PDAC by regulating PNI.