Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
Hideaki Ijichi, … , Masao Omata, Harold L. Moses
Hideaki Ijichi, … , Masao Omata, Harold L. Moses
Published September 19, 2011
Citation Information: J Clin Invest. 2011;121(10):4106-4117. https://doi.org/10.1172/JCI42754.
View: Text | PDF
Research Article Oncology

Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium–specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.

Authors

Hideaki Ijichi, Anna Chytil, Agnieszka E. Gorska, Mary E. Aakre, Brian Bierie, Motohisa Tada, Dai Mohri, Koji Miyabayashi, Yoshinari Asaoka, Shin Maeda, Tsuneo Ikenoue, Keisuke Tateishi, Christopher V.E. Wright, Kazuhiko Koike, Masao Omata, Harold L. Moses

×

Figure 5

Cxc chemokines from Kras+Tgfbr2KO PDAC cells induce Ctgf expression in pancreatic fibroblasts in the tumor microenvironment.

Options: View larger image (or click on image) Download as PowerPoint
Cxc chemokines from Kras+Tgfbr2KO PDAC cells induce Ctgf expression in p...
(A) Representative figures from Ctgf immunohistochemistry. Ctgf was strongly expressed in the stromal area adjacent to the PDAC tumor epithelia and the tumor cells at the invasive front in Kras+Tgfbr2KO mice. Scale bars: 125 μm. (B) QRT-PCR showed that Ctgf mRNA expression was significantly higher in the pancreatic fibroblasts than in Kras+Tgfbr2KO PDAC cells, and the Cxc chemokines induced Ctgf expression in the fibroblasts. Cells were incubated with or without 100 ng/ml Cxcl1, -2, or -5 for 6 hours, then the RNA was extracted. The expression ratio of Ctgf to Gapdh is calculated. (C) QRT-PCR showed that CM from Kras+Tgfbr2KO PDAC cells induced Ctgf expression in the pancreatic fibroblasts in a Cxcr2-dependent manner. Cells were incubated with the indicated CM and with various concentrations of repertaxin (Reper; 0.1–200 μM) or SB225002 (SB; 0.01–1 μM) for 6 hours, then the RNA was extracted. The data of cells without CM were set as 1. (D) QRT-PCR showed that the Cxcl-induced Ctgf upregulation in the pancreatic fibroblasts was TGF-β signal dependent. The pancreatic fibroblasts were incubated with or without Cxcl1, -2, and -5 (0–100 ng/ml each) and with or without 10 μM Tgfbr1 inhibitor SB431542 for 24 hours, then the RNA was extracted. The expression ratio of Ctgf to Gapdh was calculated. *P < 0.05; **P < 0.01; ***P < 0.001.