The Hepatic Microenvironment and TRAIL-R2 Impact Outgrowth of Liver Metastases in Pancreatic Cancer after Surgical Resection.

Lauritz Miarka,Jan-Hendrik Egberts,Ole Helm,Lennart Lenk,Dörthe Holdhof,Anna Trauzold,Sascha Rahn,Charlotte Hauser,Susanne Sebens,Wolfgang Mikulits,Silje Beckinger,Jan-Paul Gundlach

doi:10.3390/cancers11060745

Abstract

Most patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative resection relapse within months, often with liver metastases. The hepatic microenvironment determines induction and reversal of dormancy during metastasis. Both tumor growth and metastasis depend on the Tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2). This study investigated the interplay of TRAIL-R2 and the hepatic microenvironment in liver metastases formation and the impact of surgical resection. Although TRAIL-R2-knockdown (PancTu-I shTR2) decreased local relapses and number of macroscopic liver metastases after primary tumor resection in an orthotopic PDAC model, the number of micrometastases was increased. Moreover, abdominal surgery induced liver inflammation involving activation of hepatic stellate cells (HSCs) into hepatic myofibroblasts (HMFs). In coculture with HSCs, proliferation of PancTu-I shTR2 cells was significantly lower compared to PancTu-I shCtrl cells, an effect still observed after switching coculture from HSC to HMF, mimicking surgery-mediated liver inflammation and enhancing cell proliferation. CXCL-8/IL-8 blockade diminished HSC-mediated growth inhibition in PancTu-I shTR2 cells, while Vascular Endothelial Growth Factor (VEGF) neutralization decreased HMF-mediated proliferation. Overall, this study points to an important role of TRAIL-R2 in PDAC cells in the interplay with the hepatic microenvironment during metastasis. Resection of primary PDAC seems to induce liver inflammation, which might contribute to outgrowth of liver metastases.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is still among the most lethal cancers with metastatic spread accounting for a majority of PDAC related deaths
Occurrence of hepatic metastasis despite successful R0 resection of the primary tumor indicates that dissemination of PDAC cells or even pre-malignant pancreatic ductal epithelial cells might be an early event in tumor development
Since micrometastases and disseminated tumor cells (DTCs) at distant sides are regarded as source of tumor relapse after surgery [40,41], micrometastatic burden in the liver was further analyzed in more detail

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is still among the most lethal cancers with metastatic spread accounting for a majority of PDAC related deaths. Because most of the patients are diagnosed with an already locally advanced or metastatic stage of the disease, only 15% are suitable for surgical intervention, the only curative therapeutic option [1]. Even those patients undergoing R0 resection mostly relapse with local recurrences or hepatic metastases within months after surgery [2]. Occurrence of hepatic metastasis despite successful R0 resection of the primary tumor indicates that dissemination of PDAC cells or even pre-malignant pancreatic ductal epithelial cells might be an early event in tumor development

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