title: Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network.
abstract: The tumor microenvironment is crucial to the progression of various malignancies. Malignant pleural mesothelioma (MPM), which originates from the pleura, grows aggressively in the thoracic cavity. Here we describe an orthotopic implantation SCID mouse model of MPM and demonstrate that α-SMA-positive fibroblast-like cells accumulate in the tumors produced by the human MPM cell lines MSTO-211H and Y-Meso-14. We assessed the interaction between MPM cells and their microenvironments, focusing on tumor-associated fibroblasts. MSTO-211H and Y-Meso-14 cells produced fibroblast growth factor-2 (FGF-2) and/or platelet-derived growth factor-AA (PDGF-AA); they also enhanced growth, migration, and production of hepatocyte growth factor (HGF) by human lung fibroblast MRC-5 cells. MRC-5 cells stimulated HGF-mediated growth and migration of MSTO-211H and Y-Meso-14 cells in an in vitro coculture system. In the orthotopic model, tumor formation by MSTO-211H and Y-Meso-14 cells was significantly inhibited by TSU-68, an inhibitor of FGF, VEGF, and PDGF receptors; imatinib, an inhibitor of PDGF receptors; and NK4, an antagonist of HGF. Histological analyses of clinical specimens from 51 MPM patients revealed considerable tumor-associated fibroblasts infiltration and expression of HGF, together with FGF-2 or PDGF-AA, in tumors. These findings indicate that MPM instigates tumor-associated fibroblasts, promoting tumor progression via a malignant cytokine network. Regulation of this cytokine network may be therapeutically useful for controlling MPM.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Bando
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Shotaro
authors.initials: S
authors.lastname: Iwakiri
authors.forename: Kazumi
authors.initials: K
authors.lastname: Itoi
authors.forename: Teruhiro
authors.initials: T
authors.lastname: Utsugi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000473:pathology*; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor