Disruption of Fibroblast Growth Factor Signal Pathway Inhibits the Growth of Synovial Sarcomas: Potential Application of Signal Inhibitors to Molecular Target Therapy

Ishibe, Tatsuya; Nakayama, Tomitaka; Okamoto, Takeshi; Aoyama, Tomoki; Nishijo, Koichi; Shibata, Kotaro R.; Shima, Yoshihiro; Nagayama, Satoshi; Katagiri, Toyomasa; Nakamura, Yusuke; Nakamura, Takashi; Toguchida, Junya

doi:10.1158/1078-0432.ccr-04-2057

Cited by 95 publications

(86 citation statements)

References 41 publications

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“…YaFuSS and HS-SY-II cells have the SYT-SSX1 fusion gene, and the others have the SYT-SSX2 fusion gene (data not shown). The properties of YaFuSS were described previously [26]. HS-SY-II was a gift from H. Sonobe (Kochi Medical School, Japan) [44], SYO-1 from A. Kawai (National Cancer Center, Japan) [29], Fuji from S. Tanaka (Hokkaido University, Japan) [37], and 1273/99 from O. Larsson (Karolinska Institute, Stockholm, Sweden).…”

Section: Methodsmentioning

confidence: 99%

“…We have reported the FGF signaling pathway is important for growth in SS cells [26]. Treatment with a FGF receptor (FGFR) induced growth arrest but failed to induce cell death, either necrotic or apoptotic [26].…”

Section: Methodsmentioning

confidence: 99%

“…Treatment with a FGF receptor (FGFR) induced growth arrest but failed to induce cell death, either necrotic or apoptotic [26]. For in vitro treatment with ATRA and an FGFR inhibitor, cells (1.0 9 10 4 ) were seeded on collagen-coated 60-mm dishes, and after their adhesion to the dishes, DMEM with 10% FBS was exchanged for DMEM with 10% FBS containing ATRA (1 or 10 lmol/L) and/or a FGFR-specific inhibitor, PD166866 (100 or 500 nmol/L) provided by Pfizer Global Research and Development (Groton, CT).…”

Section: Methodsmentioning

confidence: 99%

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Neuronal Differentiation of Synovial Sarcoma and Its Therapeutic Application

Ishibe

Nakayama

Aoyama

et al. 2008

Clin Orthop Relat Res

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Synovial sarcoma is a rare sarcoma of unknown histologic origin. We previously reported the gene expression profile of synovial sarcoma was closely related to that of malignant peripheral nerve sheath tumors, and the fibroblast growth factor (FGF) signal was one of the main growth signals in synovial sarcoma. Here we further demonstrate the neural origin of synovial sarcoma using primary tumors and cell lines. The expression of neural tissuerelated genes was confirmed in synovial sarcoma tumor tissues, but the expression of some genes was absent in synovial sarcoma cell lines. Treatment of synovial sarcoma cell lines with BMP4 or FGF2 enhanced or restored the expression of neural tissue-related genes and induced a neuron-like morphology with positive Tuj-1 expression. Treatment with all-trans-retinoic acid also induced the expression of neural tissue-related genes in association with growth inhibition, which was not observed in other cell lines except a malignant peripheral nerve sheath tumor cell line. A growth-inhibitory effect of all-trans-retinoic acid was also observed for xenografted tumors in athymic mice. The simultaneous treatment with FGF signal inhibitors enhanced the growth-inhibitory effect of all-trans-retinoic acid, suggesting the combination of growth signaling inhibition and differentiation induction could be a potential molecular target for treating synovial sarcoma.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Neuronal Differentiation of Synovial Sarcoma and Its Therapeutic Application

Ishibe

Nakayama

Aoyama

et al. 2008

Clin Orthop Relat Res

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“…Our group has also identified such markers using a custom-made cDNA microarray consisting of 23 040 genes in various types of malignant tumors (Nagayama et al, 2002). As for synovial sarcomas, we have identified fibroblast growth factor (Ishibe et al, 2005), Wnt-FZD10 (frizzled homolog 10) (Nagayama et al, 2005) and retinoic acid signals as molecular targets in synovial sarcomas (Ishibe et al, 2008). For other types of tumors, however, the identification of tumor-specific markers is made difficult by small numbers of cases.…”

Section: Introductionmentioning

confidence: 99%

Identification of AFAP1L1 as a prognostic marker for spindle cell sarcomas

et al. 2011

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Spindle cell sarcomas consist of tumors with different biological features, of which distant metastasis is the most ominous sign for a poor prognosis. However, metastasis is difficult to predict on the basis of current histopathological analyses. We have identified actin filament-associated protein 1-like 1 (AFAP1L1) as a candidate for a metastasis-predicting marker from the gene expression profiles of 65 spindle cell sarcomas. A multivariate analysis determined that AFAP1L1 was an independent factor for predicting the occurrence of distant metastasis (P ¼ 0.0001), which was further confirmed in another set of 41 tumors by a quantitative mRNA expression analysis. Immunohistochemical staining using paraffin-embedded tumor tissues revealed that the metastasis-free rate was significantly better in tumors negative for AFAP1L1 (P ¼ 0.0093 by log-rank test). Knocking down the AFAP1L1 gene in sarcoma cells resulted in inhibition of the cell invasion, and forced expression of AFAP1L1 in immortalized human mesenchymal stem cells induced anchorage-independent growth and increased cell invasiveness with high activity levels of matrix metallopeptidase. Furthermore, tumor growth in vivo was accelerated in AFAP1L1-transduced sarcoma cell lines. These results suggest that AFAP1L1 has a role in the progression of spindle cell sarcomas and is a prognostic biomarker.

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“…The key mitogenic pathway, mitogen-activated protein kinase (MAPK), is known to be the major downstream signaling pathway of FGF8b (Ishibe et al, 2005). Here, we examined whether FGF8b signals through MAPK in the context of EBV influence.…”

Section: Fgf8b Activates Mapk In Npc Cellsmentioning

confidence: 99%

FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

et al. 2010

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The fibroblast growth factor 8b (FGF8b) oncogene is known to be primarily involved in the tumorigenesis and progression of hormone-related cancers. Its role in other epithelial cancers has not been investigated, except for esophageal cancer, in which FGF8b overexpression was mainly found in tumor biopsies of male patients. These observations were consistent with previous findings in these cancer types that the male sex-hormone androgen is responsible for FGF8b expression. Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer of head and neck commonly found in Asia. It is etiologically associated with Epstein-Barr Virus (EBV) infection, inflammatory tumor microenvironment and relatively higher male predominance. Here, we reported for the first time that FGF8b is overexpressed in this EBV-associated non-hormone-related cancer of the head and neck, NPC. More importantly, overexpression of FGF8b mRNA and protein was detected in a large majority of NPC tumors from both male and female genders, in addition to multiple NPC cell lines. We hypothesized that FGF8b overexpression may contribute to NPC tumorigenesis. Using EBV-associated NPC cell lines, we demonstrated that specific knockdown of FGF8b by small interfering RNA inhibited cell proliferation, migration and invasion, whereas exogenous FGF8b stimulated these multiple phenotypes. Further mechanistic investigation revealed that in addition to NF-jB signaling (a major inflammatory signaling pathway known to be activated in NPC), an important EBV oncoprotein, the latent membrane protein 1 (LMP1), was found to be a direct inducer of FGF8b overexpression in NPC cells, whereas androgen (testosterone) has minimal effect on FGF8b expression in EBVassociated NPC cells. In summary, our study has identified LMP1 as the first viral oncogene capable of directly inducing FGF8b (an important cellular oncogene) expression in human cancer cells. This novel mechanism of viral-mediated FGF8 upregulation may implicate a new role of oncoviruses in human carcinogenesis.

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Disruption of Fibroblast Growth Factor Signal Pathway Inhibits the Growth of Synovial Sarcomas: Potential Application of Signal Inhibitors to Molecular Target Therapy

Cited by 95 publications

References 41 publications

Neuronal Differentiation of Synovial Sarcoma and Its Therapeutic Application

Neuronal Differentiation of Synovial Sarcoma and Its Therapeutic Application

Identification of AFAP1L1 as a prognostic marker for spindle cell sarcomas

FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

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