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

被引：77

作者：

Sano, Makoto ^{[1
,2
]}

Ijichi, Hideaki ^{[1
,3
]}

Takahashi, Ryota ^{[1
]}

Miyabayashi, Koji ^{[1
]}

Fujiwara, Hiroaki ^{[1
]}

Yamada, Tomoharu ^{[1
]}

Kato, Hiroyuki ^{[1
]}

Nakatsuka, Takuma ^{[1
]}

Tanaka, Yasuo ^{[1
]}

Tateishi, Keisuke ^{[1
]}

Morishita, Yasuyuki ^{[4
]}

Moses, Harold L. ^{[5
]}

Isayama, Hiroyuki ^{[1
,6
]}

Koike, Kazuhiko ^{[1
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan

[2] Nihon Univ, Sch Med, Dept Pathol & Microbiol, Div Human Pathol,Itabashi Ku, 30-1 Oyaguchikamicho, Tokyo 1738610, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Clin Nutr Therapy, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan

[4] Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan

[5] Vanderbilt Univ, Vanderbilt Ingram Comprehens Canc Ctr, 691 Preston Bldg, Nashville, TN 37232 USA

[6] Juntendo Univ, Sch Med, Dept Gastroenterol, Bunkyo Ku, 3-1-3 Hongo, Tokyo 1138431, Japan

来源：

ONCOGENESIS | 2019年 / 8卷 / 2期

关键词：

IN-VITRO; CXCR2; GROWTH; ANGIOGENESIS; PROGRESSION; SUPPRESSES; EXPRESSION; RECEPTORS; PATHWAYS; LIGANDS;

D O I：

10.1038/s41389-018-0117-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-beta 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.

引用

页数：12

共 1 条

[1] Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
Ijichi, Hideaki
Chytil, Anna
Gorska, Agnieszka E.
Aakre, Mary E.
Bierie, Brian
Tada, Motohisa
Mohri, Dai
Miyabayashi, Koji
Asaoka, Yoshinari
Maeda, Shin
Ikenoue, Tsuneo
Tateishi, Keisuke
Wright, Christopher V. E.
Koike, Kazuhiko
Omata, Masao
Moses, Harold L.
JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (10) : 4106 - 4117

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