This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohuchida, K. Articles by Tanaka, M. Search for Related Content PubMed PubMed Citation Articles by Ohuchida, K. Articles by Tanaka, M.

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

¹ Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and ² Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medical Science, Suita, Osaka, Japan

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.

This article has been cited by other articles:

				T. Moriyama, K. Ohuchida, K. Mizumoto, J. Yu, N. Sato, T. Nabae, S. Takahata, H. Toma, E. Nagai, and M. Tanaka MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance Mol. Cancer Ther., May 1, 2009; 8(5): 1067 - 1074. [Abstract] [Full Text] [PDF]

				M. R. Loebinger, E. K. Sage, and S. M. Janes Mesenchymal Stem Cells as Vectors for Lung Disease Proceedings of the ATS, August 15, 2008; 5(6): 711 - 716. [Abstract] [Full Text] [PDF]

				T. Egami, K. Ohuchida, K. Mizumoto, M. Onimaru, H. Toma, S. Nishio, E. Nagai, K. Matsumoto, T. Nakamura, and M. Tanaka Radiation Enhances Adenoviral Gene Therapy in Pancreatic Cancer via Activation of Cytomegalovirus Promoter and Increased Adenovirus Uptake Clin. Cancer Res., March 15, 2008; 14(6): 1859 - 1867. [Abstract] [Full Text] [PDF]

				J. Wels, R. N. Kaplan, S. Rafii, and D. Lyden Migratory neighbors and distant invaders: tumor-associated niche cells Genes & Dev., March 1, 2008; 22(5): 559 - 574. [Abstract] [Full Text] [PDF]

				R. F. Hwang, T. Moore, T. Arumugam, V. Ramachandran, K. D. Amos, A. Rivera, B. Ji, D. B. Evans, and C. D. Logsdon Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression Cancer Res., February 1, 2008; 68(3): 918 - 926. [Abstract] [Full Text] [PDF]

				T. Kaneko, Z. Zhang, M. G. Mantellini, E. Karl, B. Zeitlin, M. Verhaegen, M. S. Soengas, M. Lingen, R. M. Strieter, G. Nunez, et al. Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth Cancer Res., October 15, 2007; 67(20): 9685 - 9693. [Abstract] [Full Text] [PDF]

				D. Liu and P. J. Hornsby Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion Cancer Res., April 1, 2007; 67(7): 3117 - 3126. [Abstract] [Full Text] [PDF]

				D. Mahadevan and D. D. Von Hoff Tumor-stroma interactions in pancreatic ductal adenocarcinoma Mol. Cancer Ther., April 1, 2007; 6(4): 1186 - 1197. [Abstract] [Full Text] [PDF]

				J.-P. Coppe, K. Kauser, J. Campisi, and C. M. Beausejour Secretion of Vascular Endothelial Growth Factor by Primary Human Fibroblasts at Senescence J. Biol. Chem., October 6, 2006; 281(40): 29568 - 29574. [Abstract] [Full Text] [PDF]

				K. Ohuchida, K. Mizumoto, T. Egami, H. Yamaguchi, K. Fujii, H. Konomi, E. Nagai, K. Yamaguchi, M. Tsuneyoshi, and M. Tanaka S100P Is an Early Developmental Marker of Pancreatic Carcinogenesis. Clin. Cancer Res., September 15, 2006; 12(18): 5411 - 5416. [Abstract] [Full Text] [PDF]

				K. Ohuchida, K. Mizumoto, S. Ohhashi, H. Yamaguchi, H. Konomi, E. Nagai, K. Yamaguchi, M. Tsuneyoshi, and M. Tanaka S100A11, A Putative Tumor Suppressor Gene, Is Overexpressed in Pancreatic Carcinogenesis. Clin. Cancer Res., September 15, 2006; 12(18): 5417 - 5422. [Abstract] [Full Text] [PDF]

				C. Blanquicett, M. W. Saif, D. J. Buchsbaum, M. Eloubeidi, S. M. Vickers, D. C. Chhieng, M. D. Carpenter, J. C. Sellers, S. Russo, R. B. Diasio, et al. Antitumor Efficacy of Capecitabine and Celecoxib in Irradiated and Lead-Shielded, Contralateral Human BxPC-3 Pancreatic Cancer Xenografts: Clinical Implications of Abscopal Effects Clin. Cancer Res., December 15, 2005; 11(24): 8773 - 8781. [Abstract] [Full Text] [PDF]

				M. C. Wilkes, H. Mitchell, S. G. Penheiter, J. J. Dore, K. Suzuki, M. Edens, D. K. Sharma, R. E. Pagano, and E. B. Leof Transforming Growth Factor-{beta} Activation of Phosphatidylinositol 3-Kinase Is Independent of Smad2 and Smad3 and Regulates Fibroblast Responses via p21-Activated Kinase-2 Cancer Res., November 15, 2005; 65(22): 10431 - 10440. [Abstract] [Full Text] [PDF]

				K. Ohuchida, K. Mizumoto, N. Ishikawa, K. Fujii, H. Konomi, E. Nagai, K. Yamaguchi, M. Tsuneyoshi, and M. Tanaka The Role of S100A6 in Pancreatic Cancer Development and Its Clinical Implication as a Diagnostic Marker and Therapeutic Target Clin. Cancer Res., November 1, 2005; 11(21): 7785 - 7793. [Abstract] [Full Text] [PDF]

				B. Grum-Schwensen, J. Klingelhofer, C. H. Berg, C. El-Naaman, M. Grigorian, E. Lukanidin, and N. Ambartsumian Suppression of Tumor Development and Metastasis Formation in Mice Lacking the S100A4(mts1) Gene Cancer Res., May 1, 2005; 65(9): 3772 - 3780. [Abstract] [Full Text] [PDF]

				M. EGEBLAD, L.E. LITTLEPAGE, and Z. WERB The Fibroblastic Coconspirator in Cancer Progression Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 383 - 388. [Abstract] [PDF]