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Parenchyma–stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF‐β/BMP4 in ameloblastoma
Author(s) -
Takebe Yuichiro,
Tsujigiwa Hidetsugu,
Katase Naoki,
Siar Chong Huat,
Takabatake Kiyofumi,
Fujii Masae,
Tamamura Ryo,
Nakano Keisuke,
Nagatsuka Hitoshi
Publication year - 2017
Publication title -
journal of oral pathology and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.887
H-Index - 83
eISSN - 1600-0714
pISSN - 0904-2512
DOI - 10.1111/jop.12467
Subject(s) - stromal cell , ameloblastoma , pathology , parenchyma , transforming growth factor , rankl , stroma , cancer research , immunohistochemistry , chemistry , biology , medicine , microbiology and biotechnology , anatomy , receptor , maxilla , activator (genetics)
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 CCN 2, TGF ‐β, and BMP 4 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 CCN 2 overexpression correlated significantly with fibrous‐type stroma, but not with myxoid‐type stroma, suggesting a role of CCN 2 in fibrosis ( P < 0.05). Recombinant CCN 2 induction of enhanced ASF proliferation in AM ‐1 medium supports this view. Conversely, BMP 4 and TGF ‐β were expressed in myxoid‐type fibroblasts, but little expression was found in parenchyma. RANKL ‐positive and CD 68‐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/ BMP 4 signaling to promote osteoclastogenesis.