Tenascin C in the Tumor-Nerve Microenvironment Enhances... : Pancreas (original) (raw)

Original Articles

Tenascin C in the Tumor-Nerve Microenvironment Enhances Perineural Invasion and Correlates With Locoregional Recurrence in Pancreatic Ductal Adenocarcinoma

Furuhashi, Satoru MD∗,†,‡; Sakaguchi, Takanori MD, PhD∗; Murakami, Tomohiro MD, PhD∗; Fukushima, Mayu MD§; Morita, Yoshifumi MD, PhD∗; Ikegami, Koji PhD†,‡; Kikuchi, Hirotoshi MD, PhD∗; Setou, Mitsutoshi MD, PhD†,‡,∥,¶; Takeuchi, Hiroya MD, PhD∗

From the ∗Second Department of Surgery

†International Mass Imaging Center

Departments of ‡Cellular and Molecular Anatomy

§Pathology

∥Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

¶Department of Anatomy, The University of Hong Kong, China.

Received for publication April 29, 2019; accepted January 16, 2020.

Address correspondence to: Takanori Sakaguchi, MD, PhD, Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan (e-mail: [email protected]).

This study was supported by a Grant-in-Aid for Scientific Research (grant number 17K10694) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was also supported by Ministry of Education, Culture, Sports, Science and Technology/Japan Society for the Promotion of Science KAKENHI (grant number JP15H05898B1) and the Imaging Platform supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan, and AMED (grant number JP18gm0910004).

The authors declare no conflict of interest.

Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pancreasjournal.com).

Abstract

Objectives

Perineural invasion is common in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. Tenascin C (TNC), an extracellular matrix glycoprotein, modulates tumor progression. We evaluated the functional roles of TNC, especially in perineural invasion of PDAC.

Methods

We examined immunohistochemical TNC expression in 78 resected PDAC specimens. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Interactions between cancer cells and nerves with TNC supplementation were investigated using an in vitro coculture model with PDAC cell line and mouse dorsal root ganglion (DRG).

Results

Tenascin C expression was predominant in perineural sites at the invasive tumor front. High perineural TNC expression in 30 patients (38%) was associated with perineural invasion, pathological T stage ≥3, and postoperative locoregional recurrence. High TNC expression was independently associated with postoperative, poor recurrence-free survival by multivariate analysis. In the in vitro coculture model, a TNC-rich matrix enhanced both PDAC cell colony extensions toward nerves and DRG axonal outgrowth toward cancer cell colonies, whereas TNC did not affect axonal outgrowth or cancer cell proliferation in separately cultured DRG and PDAC cells.

Conclusions

Strong perineural TNC expression indicated poor prognosis with locoregional recurrence. The neurotropism of TNC-induced PDAC suggests that TNC is a potential PDAC therapeutic target.