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Abstract
Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.
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1 The University of Tokyo, Department of Gastroenterology, Graduate School of Medicine, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)
2 The University of Tokyo, Department of Gastroenterology, Graduate School of Medicine, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); Nihon University School of Medicine, Division of Medical Research Planning and Development, Tokyo, Japan (GRID:grid.260969.2) (ISNI:0000 0001 2149 8846)
3 Nihon University School of Medicine, Division of Medical Research Planning and Development, Tokyo, Japan (GRID:grid.260969.2) (ISNI:0000 0001 2149 8846)
4 The University of Tokyo, Department of Molecular Pathology, Graduate School of Medicine, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)
5 The University of Tokyo, Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)
6 The University of Tokyo, Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); Jichi Medical University School of Medicine, Division of Cardiovascular Medicine, Department of Medicine, Tochigi, Japan (GRID:grid.410804.9) (ISNI:0000000123090000)
7 Vanderbilt University, Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217)
8 Juntendo University School of Medicine, Department of Gastroenterology, Tokyo, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738)