Blocking CXCLs-CXCR2 axis in tumor-stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment

Makoto Sano; Hideaki Ijichi; Ryota Takahashi; Koji Miyabayashi; Hiroaki Fujiwara; Tomoharu Yamada; Hiroyuki Kato; Takuma Nakatsuka; Yasuo Tanaka; Keisuke Tateishi; Yasuyuki Morishita; Harold L Moses; Hiroyuki Isayama; Kazuhiko Koike

doi:10.1038/s41389-018-0117-8

Blocking CXCLs-CXCR2 axis in tumor-stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment

Oncogenesis. 2019 Jan 18;8(2):8. doi: 10.1038/s41389-018-0117-8.

Authors

Makoto Sano^{1

2}, Hideaki Ijichi^{3

4}, Ryota Takahashi¹, Koji Miyabayashi¹, Hiroaki Fujiwara¹, Tomoharu Yamada¹, Hiroyuki Kato¹, Takuma Nakatsuka¹, Yasuo Tanaka¹, Keisuke Tateishi¹, Yasuyuki Morishita⁵, Harold L Moses⁶, Hiroyuki Isayama^{1

7}, Kazuhiko Koike¹

Affiliations

¹ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
² Division of Human Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
³ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. hideijichi-gi@umin.ac.jp.
⁴ Department of Clinical Nutrition Therapy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. hideijichi-gi@umin.ac.jp.
⁵ Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
⁶ Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, 691 Preston Building, Nashville, TN, 37232, USA.
⁷ Department of Gastroenterology, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal reaction (desmoplasia). We have previously reported that mice with conditional Kras^G12D mutation and knockout of TGF-β receptor type II (Tgfbr2), PKF mice, develop PDAC with desmoplasia modulated by CXC chemokines that are produced by PDAC cells through tumor-stromal interaction. In this study, we further discovered that PDAC and cancer-associated fibroblast (CAF) accelerated each other's invasion and migration through the CXC chemokines-receptor (CXCLs-CXCR2) axis. Heterozygous knockout of Cxcr2 in PKF mice (PKF2h mice) prolonged survival and inhibited both tumor angiogenesis and PDAC microinvasion. Infiltration of neutrophils, myeloid-derived suppressor cells (MDSCs), and arginase-1⁺ M2-like tumor-associated macrophages (TAMs) significantly decreased in the tumors of PKF2h mice, whereas inducible nitric oxide synthase (iNOS)⁺ M1-like TAMs and apoptotic tumor cells markedly increased, which indicated that blockade of the CXCLs-CXCR2 axis resulted in a shift of immune-inflammatory microenvironment. These results suggest that blocking of the CXCLs-CXCR2 axis in tumor-stromal interactions could be a therapeutic approach against PDAC progression.