Interleukin-6/soluble interleukin-6 receptor signaling attenuates proliferation and invasion, and induces morphological changes of a newly established pleomorphic malignant fibrous histiocytoma cell line.
Pleomorphic malignant fibrous histiocytoma (MFH) is occasionally associated with inflammatory paraneoplastic syndrome (PNS). Recently, we reported that interleukin (IL)-6, one of the candidate cytokines, which induces such systemic inflammatory reaction, may be a tumor-associated factor involved in the pathogenesis and its clinical manifestations of MFH. In the local microenvironment, tumor-induced inflammatory reaction may play a role favoring tumor progression. To clarify the biological relevance of IL-6 in MFH, we established a human MFH cell line, named MIPS-2, derived from a resected specimen of a patient presenting with PNS. In this patient, the serum IL-6 level ran parallel to the disease course: elevated serum IL-6 concentration normalized immediately after radical surgery, and re-elevation occurred on tumor recurrence. MIPS-2 presented pleomorphic appearance, severe nuclear abnormalities with prominent nucleoli, and tumorigenesis in nude mice. MIPS-2 expressed IL-6, IL-6 receptor (IL-6R), and glycoprotein 130 (gp130) but lacked the soluble form of IL-6R (sIL-6R), as determined by flow cytometry and reverse transcriptase-polymerase chain reaction analyses. Stimulation of MIPS-2 with IL-6 combined with exogenous sIL-6R induced phosphorylation of both signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK), decreased cell proliferation, attenuated invasion, and induced morphological changes. Collectively, these data suggested that the IL-6/sIL-6R signaling pathway plays a pivotal role for proliferation, invasion, and morphology of MFH via STAT3 and MAPK pathway as autocrine and/or paracrine manner, and proposed the therapeutic potential for the use of both anti-growth factor and proinflammatory cytokine-targeting strategies to combat devastating MFH.
Nakanishi
Hirofumi
H
Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan. h-nakanishi@mvf.biglobe.ne.jp.
Yoshioka
Kiyoko
K
Joyama
Susumu
S
Araki
Nobuhito
N
Myoui
Akira
A
Ishiguro
Shingo
S
Ueda
Takafumi
T
Yoshikawa
Hideki
H
Itoh
Kazuyuki
K
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D018219:Histiocytoma, Benign Fibrous / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D010257:Paraneoplastic Syndromes / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D020929:Mitogen-Activated Protein Kinase Kinases