TY - JOUR TI - Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer AU - Takahashi, Ryota AU - Ijichi, Hideaki AU - Sano, Makoto AU - Miyabayashi, Koji AU - Mohri, Dai AU - Kim, Jinsuk AU - Kimura, Gen AU - Nakatsuka, Takuma AU - Fujiwara, Hiroaki AU - Yamamoto, Keisuke AU - Kudo, Yotaro AU - Tanaka, Yasuo AU - Tateishi, Keisuke AU - Nakai, Yousuke AU - Morishita, Yasuyuki AU - Soma, Katsura AU - Takeda, Norihiko AU - Moses, Harold L. AU - Isayama, Hiroyuki AU - Koike, Kazuhiko T2 - Scientific Reports AB - 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. DA - 2020/12/03/ PY - 2020 DO - 10.1038/s41598-020-78320-3 DP - www.nature.com VL - 10 IS - 1 SP - 21194 LA - en SN - 2045-2322 UR - https://www.nature.com/articles/s41598-020-78320-3 Y2 - 2020/12/03/17:00:01 ER -