Inhibition of transforming growth factor-β signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor.
Interaction between tumor cells and stromal fibroblasts plays essential roles in tumor progression. However, its detailed molecular mechanism remains unclear. To understand the mechanism, we investigated molecules mediating this interaction using the three-dimensional (3D) co-culture system of Panc-1 pancreatic carcinoma cells with normal fibroblasts. When the two kinds of cells were placed on the top of collagen gel, the tumor cells scattered into the fibroblast layer, apparently undergoing epithelial-mesenchymal transition. When fibroblasts were placed within collagen gel, Panc-1 cells actively invaded into the collagen gel, extending a microtubule-based long protrusion. Although transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) individually stimulated the tumor cell invasion into collagen gel without fibroblasts, TGF-β signaling inhibitors (SB431542 and LY2157299) significantly enhanced the Panc-1 cell invasion in the 3D co-culture with fibroblasts. Experiments with HGF/Met signaling inhibitors or with the fibroblast conditioned medium revealed that HGF was a major invasion-promoting factor secreted from fibroblasts and SB431542 increased the HGF secretion by blocking the HGF-suppressing activity of cancer cell-derived TGF-β. These results indicate that HGF and TGF-β are critical regulators for both tumor-stroma interaction and tumor invasion. The results also suggest that TGF-β signaling inhibitors may promote tumor progression under some pathological conditions.
Graduate School of Integrated Science, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan; Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Japan.
Jun
J
Oyanagi
Graduate School of Integrated Science, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan; Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Japan.
Nako
N
Kojima
Graduate School of Integrated Science, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan; Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Japan.
Haruki
H
Sato
Graduate School of Integrated Science, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan; Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Japan.
Shouichi
S
Higashi
Molecular Cell Biology Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan.
Keiji
K
Kikuchi
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Katsuya
K
Sakai
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Kunio
K
Matsumoto
Graduate School of Integrated Science, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan; Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Japan. Electronic address: miyazaki@yokohama-cu.ac.jp.
Kaoru
K
Miyazaki
D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015233:Models, Statistical; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; C066855:HGF protein, human; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D003094:Collagen
Cancer-associated fibroblast (CAF); Collagen; HGF; TGF-β; Tumor invasion; Tumor stroma