Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer

• Published in: Scientific reports 2020-12, Vol.10 (1), p.21194, Article 21194
• Main Authors: Takahashi, Ryota, Ijichi, Hideaki, Sano, Makoto, Miyabayashi, Koji, Mohri, Dai, Kim, Jinsuk, Kimura, Gen, Nakatsuka, Takuma, Fujiwara, Hiroaki, Yamamoto, Keisuke, Kudo, Yotaro, Tanaka, Yasuo, Tateishi, Keisuke, Nakai, Yousuke, Morishita, Yasuyuki, Soma, Katsura, Takeda, Norihiko, Moses, Harold L., Isayama, Hiroyuki, Koike, Kazuhiko
• Format: Article
• Language: English
• Subjects: 631/67/1059/2326; 631/67/1059/602; 631/67/1059/99; 631/67/1504/1713; 631/67/2324; 631/67/327; Animals; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Biomarkers, Tumor - blood; Cancer therapies; Cell adhesion & migration; Cell adhesion molecules; Cell culture; Cell Line, Tumor; Chemotherapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug Resistance, Neoplasm - physiology; Gemcitabine; Genetic engineering; Humanities and Social Sciences; Humans; Macrophages; Macrophages - pathology; Metastases; Mice; multidisciplinary; Pancreatic cancer; Pancreatic islet transplantation; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Prognosis; Science; Science (multidisciplinary); Tumor cells; Tumors; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - blood; Vascular Cell Adhesion Molecule-1 - physiology; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-78320-3

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.