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

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Figure 6

Tumor-stromal interaction accelerates PDAC progression in a Cxcr2-dependent manner in vivo.

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Tumor-stromal interaction accelerates PDAC progression in a Cxcr2-depend...
(A) Growth of subcutaneous tumor allograft. K399 PDAC cells (3 × 106) or a mixture of 1.5 × 106 PDAC cells and 1.5 × 106 K643f fibroblasts were subcutaneously injected into nude mice. The mixture showed faster tumor growth. n = 8/group. (B) H&E staining of subcutaneous tumors. Scale bar: 200 μm (insets, 100 μm). (C) Growth of subcutaneous mixed-cell tumor allograft with or without CXCR2 antagonist. A mixture of 1.5 × 106 K399 PDAC cells and 1.5 × 106 K643f fibroblasts was subcutaneously injected into nude mice, and 1 week later, 30 mg/kg repertaxin or PBS was injected subcutaneously 5 days/week. Inhibition of Cxcr2 slowed tumor growth. n = 7/group. Tumor volume of day 1 was assigned as 1, and relative volume is shown. (D) Growth of subcutaneous mixed-cell tumor allograft with or without Cxcr2 knockdown. A mixture of Cxcr2 wild-type PDAC cells (K399) and Cxcr2-knockdown fibroblasts (K643f) (1.0 × 106 each) (group C) or a mixture of Cxcr2-knockdown K399 and Cxcr2 wild-type K643f (1.0 × 106 each) (group D) was subcutaneously injected into nude mice. n = 12/group. Cxcr2 knockdown in fibroblasts slowed tumor growth. The tumor volume was calculated by the following equation: volume = 0.5 × L × W2. *P < 0.05; **P < 0.01; ***P < 0.001.