Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts: fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production.
The intensive stromal reaction is one of characteristics of pancreatic exocrine carcinoma. The mutual interaction between pancreatic cancer cells and orthotopic tumor-derived fibroblasts have not been clarified yet. In this study, we sought to elucidate the mechanism underlying the tumor-stromal interaction with an in vitro coculture experimental system. Considerable strong c-Met expression was detected in seven out ten lines of human pancreatic carcinoma cells, as determined by Western blotting. For hepatocyte growth factor (HGF)-production, however, none or only trace amounts of HGF could be detected in those ten cell lines. Of the two lots of tumor-derived fibroblasts obtained from two pancreatic cancer patients, the fibroblasts capable to produce HGF could initiate an apparent invasion-stimulating response in strong c-Met-expressed Suit-2 and Panc-1 cells but not in faint expressed Mia PaCa-2 and BxPC-3 cells. A specialized HGF antagonist, NK4 would effectively inhibit the fibroblast-mediated invasive growth, thus proving the key role of the paracrine-fashioned HGF/c-Met pathway in the tumor-stromal interaction. On the other hand, the regulative action of cancer cells on HGF expression of fibroblasts was also investigated using direct or indirect coculture systems. For the fibroblasts that originally did not produce HGF, cancer cells failed to show any HGF-inductive effect. For the HGF-producing fibroblasts, despite of somewhat upregulation or downregulation in fibroblast HGF expression, the feedback regulation by studied pancreatic cancer cells in both coculture modes were relatively limited. This in vitro study sketched out the interaction between cancerous and stromal compartments with an emphasis on HGF/c-Met signal pathway, thus possibly helping to unveil the more complicated mutual modulation in vivo between pancreatic cancer and host mesenchymal tissues.
Qian
Li-Wu
LW
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. qianlw@surg1.med.kyushu-u.ac.jp
Mizumoto
Kazuhiro
K
Maehara
Naoki
N
Ohuchida
Kenoki
K
Inadome
Naoki
N
Saimura
Michiyo
M
Nagai
Eishi
E
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Tanaka
Masao
M
D015153:Blotting, Western; D018920:Coculture Techniques / Q000379:methods; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met