Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions.
Radiotherapy represents a major treatment option for patients with pancreatic cancer, but recent evidence suggests that radiation can promote invasion and metastasis of cancer cells. Interactions between cancer cells and surrounding stromal cells may play an important role in aggressive tumor progression. In the present study, we investigated the invasive phenotype of pancreatic cancer cells in response to coculture with irradiated fibroblasts. Using in vitro invasion assay, we demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of pancreatic cancer cells and, surprisingly, the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. The hepatocyte growth factor (HGF) secretion from fibroblasts remained unchanged after irradiation, whereas exposure of pancreatic cancer cells to supernatant from irradiated fibroblasts resulted in increased phosphorylation of c-Met (HGF receptor) and mitogen-activated protein kinase activity, possibly or partially via increased expression of c-Met. We also demonstrated that scattering of pancreatic cancer cells was accelerated by the supernatant from irradiated fibroblasts. The enhanced invasiveness of pancreatic cancer cells induced by coculture with irradiated fibroblasts was completely blocked by NK4, a specific antagonist of HGF. These data suggest that invasive potential of certain pancreatic cancer cells is enhanced by soluble mediator(s) released from irradiated fibroblasts possibly through up-regulation of c-Met expression/phosphorylation and mitogen-activated protein kinase activity in pancreatic cancer cells. Our present findings further support the potential use of NK4 during radiotherapy for patients with pancreatic cancer.
Ohuchida
Kenoki
K
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mizumoto
Kazuhiro
K
Murakami
Mitsuhiko
M
Qian
Li-Wu
LW
Sato
Norihiro
N
Nagai
Eishi
E
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Tanaka
Masao
M
D002450:Cell Communication / Q000502:physiology / Q000528:radiation effects*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects*; D006133:Growth Substances / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000528:radiation effects
D006133:Growth Substances; C066855:HGF protein, human; D008934:Mitogens; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases