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J Oral Pathol Med. 2017 Jan;46(1):67-75. doi: 10.1111/jop.12467. Epub 2016 Jun 21.

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

Author information

1
Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
2
Department of Life Science, Faculty of Science, Okayama University of Science, Okayama, Japan.
3
Department of Molecular and Developmental Biology, Kawasaki Medical School, Okayama, Japan.
4
Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
5
Department of Histology, Nihon University School of Dentistry, Matsudo, Japan.

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.

KEYWORDS:

ameloblastoma; ameloblastoma-derived cell lines cells; bone morphogenetic protein-4; connective tissue growth factor; transforming growth factor-beta

PMID:
27327904
DOI:
10.1111/jop.12467
[Indexed for MEDLINE]

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