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Fulltext Three-dimensional cell culture at the frontiers of in vitro cancer research: present perspectives

Lee, Soo Leng, Zainal Ariff Abdul Rahman, Tsujigiwa, Hidetsugu, Takabatake, Kiyofumi, Nakano, Keisuke, Chai, Wen Lin, et al.

Ann Dent, 2016;23(1):13-22.
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In recent years, three-dimensional (3D) in vitro cell culture models have earned great attention, especially in the field of human cancer disease modelling research as they provide a promising alternative towards the conventional two-dimensional (2D) monolayer culture of cells with improved tissue organization. In 2D cell culture systems, the complexity of cells on a planar surface does not accurately reflects the in vivo cellular microenvironment. Cells propagated in 3D cell culture model, on the other hand, exhibit physiologically relevant cell-to-cell interactions and cell-to-extracellular matrix (ECM) interactions, important in maintaining a normal homeostasis and specificity of tissues. This review gives an overview on 2D models and their limitations, followed by 3D cell culture models, their advantages, drawbacks and challenges in present perspectives. The review also highlights the dissimilarities of 2D and 3D models and the applicability of 3D models in current cancer research
RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance

Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH

Oral Surg Oral Med Oral Pathol Oral Radiol, 2015 Jan;119(1):83-91.
PMID: 25446507 DOI: 10.1016/j.oooo.2014.09.017

To determine the distribution patterns of bone resorption regulators, receptor activator of nuclear factor κ-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in recurrent ameloblastoma (RAs) and to clarify their impact on the biologic behavior of these neoplasms.
Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma

Siar CH, Nagatsuka H, Han PP, Buery RR, Tsujigiwa H, Nakano K, et al.

J Oral Pathol Med, 2012 Apr;41(4):332-9.
PMID: 22077561 DOI: 10.1111/j.1600-0714.2011.01104.x

Canonical and non-canonical Wnt signaling pathways modulate diverse cellular processes during embryogenesis and post-natally. Their deregulations have been implicated in cancer development and progression. Wnt signaling is essential for odontogenesis. The ameloblastoma is an odontogenic epithelial neoplasm of enamel organ origin. Altered expressions of Wnts-1, -2, -5a, and -10a are detected in this tumor. The activity of other Wnt members remains unclarified.
Notch4 overexpression in ameloblastoma correlates with the solid/multicystic phenotype

Siar CH, Nagatsuka H, Chuah KS, Rivera RS, Nakano K, Ng KH, et al.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2010 Aug;110(2):224-33.
PMID: 20659700 DOI: 10.1016/j.tripleo.2010.03.009

Notch signaling has been implicated in cell fate decisions during odontogenesis and tumorigenesis of some odontogenic neoplasms; however, its role in solid/multicystic (SA), unicystic (UA), and recurrent (RA) ameloblastoma remains unclear. The aim of this study was to determine Notch receptor and ligand expressions in these subtypes and to speculate on their significance.
Differential expression of Notch receptors and their ligands in desmoplastic ameloblastoma

Siar CH, Nakano K, Han PP, Nagatsuka H, Ng KH, Kawakami T

J Oral Pathol Med, 2010 Aug 1;39(7):552-8.
PMID: 20337864 DOI: 10.1111/j.1600-0714.2009.00871.x

In mammals, the Notch gene family encodes four receptors (Notch1-4), and all of them are important for cell fate decisions. Notch signaling pathway plays an essential role in tooth development. The ameloblastoma, a benign odontogenic epithelial neoplasm, histologically recapitulates the enamel organ at bell stage. Notch has been detected in the plexiform and follicular ameloblastoma. Its activity in the desmoplastic ameloblastoma is unknown.
Parenchyma-stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF-β/BMP4 in ameloblastoma

Takebe Y, Tsujigiwa H, Katase N, Siar CH, Takabatake K, Fujii M, et al.

J Oral Pathol Med, 2017 Jan;46(1):67-75.
PMID: 27327904 DOI: 10.1111/jop.12467

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.
Invadopodia proteins, cortactin, N-WASP and WIP differentially promote local invasiveness in ameloblastoma

Siar CH, Rahman ZA, Tsujigiwa H, Mohamed Om Alblazi K, Nagatsuka H, Ng KH

J Oral Pathol Med, 2016 Sep;45(8):591-8.
PMID: 26752341 DOI: 10.1111/jop.12417

BACKGROUND: Cell migration and invasion through interstitial tissues are dependent upon several specialized characteristics of the migratory cell notably generation of proteolytic membranous protrusions or invadopodia. Ameloblastoma is a benign odontogenic epithelial neoplasm with a locally infiltrative behaviour. Cortactin and MMT1-MMP are two invadopodia proteins implicated in its local invasiveness. Other invadopodia regulators, namely N-WASP, WIP and Src kinase remain unclarified. This study addresses their roles in ameloblastoma.
MATERIALS AND METHOD: Eighty-seven paraffin-embedded ameloblastoma cases (20 unicystic, 47 solid/multicystic, 3 desmoplastic and 17 recurrent) were subjected to immunohistochemistry for expression of cortactin, N-WASP, WIP, Src kinase and F-actin, and findings correlated with clinicopathological parameters.
RESULTS: Invadopodia proteins (except Src kinase) and F-actin were widely detected in ameloblastoma (cortactin: n = 73/87, 83.9%; N-WASP: n = 59/87; 67.8%; WIP: n = 77/87; 88.5%; and F-actin: n = 87/87, 100%). Protein localization was mainly cytoplasmic and/or membranous, and occasionally nuclear for F-actin. Cortactin, which functions as an actin-scaffolding protein, demonstrated significantly higher expression levels within ameloblastoma tumoral epithelium than in stroma (P < 0.05). N-WASP, which coordinates actin polymerization and invadopodia-mediated extracellular matrix degradation, was overexpressed in the solid/multicystic subtype (P < 0.05). WIP, an upstream regulator of N-WASP, and F-actin were significantly upregulated along the tumour invasive front compared to tumour centres (P < 0.05). Except for males with cortactin overexpression, other clinical parameters (age, ethnicity and anatomical site) showed no significant correlations.
CONCLUSIONS: Present results suggest that local invasiveness of ameloblastoma is dependent upon the migratory potential of its tumour cells as defined by their distribution of cortactin, N-WASP and WIP in correlation with F-actin cytoskeletal dynamics.
Fulltext Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis

Kawai H, Tsujigiwa H, Siar CH, Nakano K, Takabatake K, Fujii M, et al.

Int J Med Sci, 2018;15(12):1406-1414.
PMID: 30275769 DOI: 10.7150/ijms.24370

Background: The tumor microenvironment and its stromal cells play an important role in cancer development and metastasis. Bone marrow-derived cells (BMDCs), a rich source of hematopoietic and mesenchymal stem cells, putatively contribute to this tumoral stroma. However their characteristics and roles within the tumor microenvironment are unclear. In the present study, BMDCs in the tumor microenvironment were traced using the green fluorescent protein (GFP) bone marrow transplantation model. Methods: C57BL/6 mice were irradiated and rescued by bone marrow transplantation from GFP-transgenic mice. Lewis lung cancer cells were inoculated into the mice to generate subcutaneous allograft tumors or lung metastases. Confocal microscopy, immunohistochemistry for GFP, α-SMA, CD11b, CD31, CD34 and CD105, and double-fluorescent immunohistochemistry for GFP-CD11b, GFP-CD105 and GFP-CD31 were performed. Results: Round and dendritic-shaped GFP-positive mononuclear cells constituted a significant stromal subpopulation in primary tumor peripheral area (PA) and metastatic tumor area (MA) microenvironment, thus implicating an invasive and metastatic role for these cells. CD11b co-expression in GFP-positive cells suggests that round/dendritic cell subpopulations are possibly BM-derived macrophages. Identification of GFP-positive mononuclear infiltrates co-expressing CD31 suggests that these cells might be BM-derived angioblasts, whereas their non-reactivity for CD34, CD105 and α-SMA implies an altered vascular phenotype distinct from endothelial cells. Significant upregulation of GFP-positive, CD31-positive and GFP/CD31 double-positive cell densities positively correlated with PA and MA (P<0.05). Conclusion: Taken together, in vivo evidence of traceable GFP-positive BMDCs in primary and metastatic tumor microenvironment suggests that recruited BMDCs might partake in cancer invasion and metastasis, possess multilineage potency and promote angiogenesis.