Parenchyma-stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF-β/BMP4 in ameloblastoma

Yuichiro Takebe, Hidetsugu Tsujigiwa, Naoki Katase, Chong Huat Siar, Kiyofumi Takabatake, Masae Fujii, Ryo Tamamura, Keisuke Nakano, Hitoshi Nagatsuka

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4 Citations (Scopus)

Abstract

Background: Tumor parenchyma-stromal interactions affect the properties of tumors and their dynamics. Our group previously showed that secreted frizzled related protein (sFRP)-2 impairs bone formation and promotes bone invasion in ameloblastoma. However, the effects of the secreted growth factors CCN2, TGF-β, and BMP4 on stromal tissues in ameloblastoma remain unclear. Materials and results: Thirty-five paraffin-embedded ameloblastoma cases, ameloblastoma-derived cell lines (AM-1), and primary cultures of ameloblastoma stromal fibroblasts (ASF) were used. Immunohistochemistry, MTT assay, Western blotting, and RT-PCR were performed on these samples. Parenchyma-stromal CCN2 overexpression correlated significantly with fibrous-type stroma, but not with myxoid-type stroma, suggesting a role of CCN2 in fibrosis (P <0.05). Recombinant CCN2 induction of enhanced ASF proliferation in AM-1 medium supports this view. Conversely, BMP4 and TGF-β were expressed in myxoid-type fibroblasts, but little expression was found in parenchyma. RANKL-positive and CD68-positive stromal cell populations were significantly greater in myxoid-type tumor areas than in fibrous-type tumor areas, while a higher Ki-67 labeling index was recorded in ameloblastoma with fibrous-type stroma. These data suggest that stromal properties influence bone resorption-related activities and growth rates, respectively. Conclusions: These results suggest that the effects of secreted growth factors are governed by ameloblastoma parenchyma-stromal interactions. CCN2 promotes fibrogenesis independent of TGF-β signaling. Absence of CCN2 expression is associated with a phenotypic switch to a myxoid-type microenvironment that is conducive for TGF-β/BMP4 signaling to promote osteoclastogenesis.

Original languageEnglish
JournalJournal of Oral Pathology and Medicine
DOIs
Publication statusAccepted/In press - 2016

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Keywords

  • Ameloblastoma
  • Ameloblastoma-derived cell lines cells
  • Bone morphogenetic protein-4
  • Connective tissue growth factor
  • Transforming growth factor-beta

ASJC Scopus subject areas

  • Cancer Research
  • Pathology and Forensic Medicine
  • Otorhinolaryngology
  • Oral Surgery
  • Periodontics

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