| セッション情報 | The 4th International ForumII Challenge to the pancreatic and biliary cancers 1. Pancreatic and biliary cancers―Challenge to the pathogenesis |
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| タイトル | IFII-1-3：Significance of CXC Chemokines/CXCR2 Axis in Pancreatic Cancer Progression |
| 演者 | Ijichi Hideaki（Department of Gastroenterology, The University of Tokyo, Japan） |
| 共同演者 | Miyabayashi Koji（Department of Gastroenterology, The University of Tokyo, Japan）, Takahashi Ryota（Department of Gastroenterology, The University of Tokyo, Japan）, Mohri Dai（Department of Gastroenterology, The University of Tokyo, Japan）, Asaoka Yoshinari（Department of Gastroenterology, The University of Tokyo, Japan）, Tateishi Keisuke（Department of Gastroenterology, The University of Tokyo, Japan）, Ikenoue Tsuneo（Department of Gastroenterology, The University of Tokyo, Japan）, Tada Minoru（Department of Gastroenterology, The University of Tokyo, Japan）, Isayama Hiroyuki（Department of Gastroenterology, The University of Tokyo, Japan）, Moses Harold L（Department of Gastroenterology, The University of Tokyo, Japan）, Koike Kazuhiko（Department of Gastroenterology, The University of Tokyo, Japan） |
| 抄録 | Pancreatic cancer is still one of the most deadly cancers. Histological feature of this cancer is abundant stroma including marked fibrosis, desmoplasia, which might be contributing to the poor prognosis through the tumor-promoting tumor microenvironment. We have established a murine pancreatic cancer model of mutant Kras expression plus knockout of TGF-β receptor II（Kras+Tgfbr2KO）, which can recapitulate the histology of human disease very well. The abundant stroma in the cancer tissue suggested an existence of active tumor-stromal interaction. The Kras+Tgfbr2KO cancer cells characteristically produced several CXC chemokines, most of which were ligands of the receptor, CXCR2. The CXC chemokines did not promote the cancer cell proliferation directly in vitro, but acted on the CXCR2 in the stromal fibroblasts, resulting in an enhanced tumor growth in vivo. This indicated an aspect of tumor-promoting tumor-stromal interaction. We treated the Kras+Tgfbr2KO mice with CXCR2 inhibitor and observed significant tumor volume inhibition and survival extension. Angiogenesis inhibition was involved in the anti-tumor effect. Next, we screened the response of stromal fibroblasts to the cancer cell-derived stimuli by analyzing the change of gene expression profile. The microarray revealed that the cancer-associated fibroblasts also produced the same CXCR2 ligands and other inflammatory cytokines in response. Conditioned media from the cancer cells induced the fibroblast migration, on the other hand, conditioned media from the fibroblasts enhanced the cancer cell invasion in vitro, which indicated that the cancer cells and fibroblasts attracted each other using secreted factors. CXC chemokines/CXCR2 axis might be important in both ways, from cancer cells to stroma, and also from stroma to cancer cells. Thus, CXC chemokines/CXCR2 axis seems highly involved in pancreatic cancer progression and might be an important candidate of therapeutic target of pancreatic cancer. |
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