Radiation to Stromal Fibroblasts Increases Invasiveness of Pancreatic Cancer Cells through Tumor-Stromal Interactions

Kenoki Ouchida, Kazuhiro Mizumoto, Mitsuhiko Murakami, Li Wu Qian, Norihiro Sato, Eishi Nagai, Kunio Matsumoto, Toshikazu Nakamura, Masao Tanaka

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3215-3222
Number of pages8
JournalCancer Research
Volume64
Issue number9
DOIs
Publication statusPublished - May 1 2004

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Pancreatic Neoplasms
Fibroblasts
Radiation
Neoplasms
Coculture Techniques
Hepatocyte Growth Factor
Mitogen-Activated Protein Kinases
Radiotherapy
Phosphorylation
Proto-Oncogene Proteins c-met
Stromal Cells
Up-Regulation
Neoplasm Metastasis
Phenotype

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Radiation to Stromal Fibroblasts Increases Invasiveness of Pancreatic Cancer Cells through Tumor-Stromal Interactions. / Ouchida, Kenoki; Mizumoto, Kazuhiro; Murakami, Mitsuhiko; Qian, Li Wu; Sato, Norihiro; Nagai, Eishi; Matsumoto, Kunio; Nakamura, Toshikazu; Tanaka, Masao.

In: Cancer Research, Vol. 64, No. 9, 01.05.2004, p. 3215-3222.

Research output: Contribution to journalArticle

Ouchida, Kenoki ; Mizumoto, Kazuhiro ; Murakami, Mitsuhiko ; Qian, Li Wu ; Sato, Norihiro ; Nagai, Eishi ; Matsumoto, Kunio ; Nakamura, Toshikazu ; Tanaka, Masao. / Radiation to Stromal Fibroblasts Increases Invasiveness of Pancreatic Cancer Cells through Tumor-Stromal Interactions. In: Cancer Research. 2004 ; Vol. 64, No. 9. pp. 3215-3222.
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