Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia

• Published in: PloS one Vol. 11; no. 8; p. e0159912
• Main Authors: Hirakawa, Toshiki, Yashiro, Masakazu, Doi, Yosuke, Kinoshita, Haruhito, Morisaki, Tamami, Fukuoka, Tatsunari, Hasegawa, Tsuyoshi, Kimura, Kenjiro, Amano, Ryosuke, Hirakawa, Kosei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03-08-2016; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Biology and Life Sciences; Cancer; Cancer cells; Carbonic anhydrase; Carbonic anhydrases; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Movement - drug effects; Colorectal cancer; Conditioning; Enzyme-linked immunosorbent assay; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - physiology; Gene expression; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia - pathology; Inhibitors; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Invasiveness; Kinases; Medical prognosis; Medicine; Medicine and Health Sciences; Metastasis; Oncology; Oxygen - pharmacology; Pancreas; Pancreas - cytology; Pancreas - drug effects; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Paracrine signalling; Polymerase chain reaction; Receptor, IGF Type 1 - metabolism; Research and Analysis Methods; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Stromal cells; Studies; Tumor cell lines; Tumor Hypoxia - physiology; Tumor Microenvironment - drug effects; Tumors; University graduates; Wound healing; Japan; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0159912

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.