| Project/Area Number |
15390119
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Fukuoka University |
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Principal Investigator |
IWASAKI Hiroshi Fukuoka University, School of Medicine, Professor, 医学部, 教授 (90101170)
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| Co-Investigator(Kenkyū-buntansha) |
NABESHIMA Kazuki Fukuoka University, School of Medicine, Professor, 医学部, 教授 (40189189)
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| Project Period (FY) |
2003 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2005: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Keywords | Bone and soft tissue tumors / molecular genetics / chromosomal abnormalities / matrix metalloproteinases (MMPs) / sarcoma- / emmprin / malignant peripheral nerve sheath / solid tumors tumors / 骨軟部腫瘍 / Imatinib / siRNA / 細胞外マトリックス / MMP / MPNST / PDGFR / 染色体 / 遺伝子異常 / CGH / molecular cytogenetics / cDNA microarray / 遺伝子 / MT1-MMP |
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| Research Abstract |
1) A new human cell line, FU-DDLS-1 established from a dedifferentiated liposarcoma exhibited immunopositive reaction for mdm2 and p53 proteins. Cytogenetically, FU-DDLS-1 displayed a hypertetraploid karyotype with giant marker chromosomes composed partly of chromosome 12 materials. CGH analysis demonstrated that a gain of 12q12-q21 detected in FU-DDLS-1 were essentially the same as those in the original sarcoma. The FU-DDLS-1 cell line may be a particularly useful model for studying the molecular pathogenesis of human dedifferentiated liposarcoma.
2) cDNA microarray analysis of malignant peripheral nerve sheath tumors (MPNST) : Survivin and tenascin C expressions were upregulated in MPNST, validated by reverse transcription polymerase chain reaction. Immunohistochemistry confirmed upregulation of survivin in MPNST at the protein level in six of eight cases compared with benign tumours. Tenascin C was also expressed at the invasive front and tumorous stroma in all MPNST cases. Survivin
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and tenascin C may be associated with the malignant potential of MPNST and could be considered as potential therapeutic targets.
3) Expression of emmprin and matrix metalloproteinases (MMPs) in peripheral nerve sheath tumors (PNSTs) : We found that emmprin and MT1-MMP may be malignant potential-related proteins in PNSTs, and that MMP-1 and 9 may help differentiation between schwannoma and neurofibroma, especially in their plexiform types. The expression patterns of MMP-1 and gelatinase B (MMP-9) could divide PNSTs into two groups : schwannoma versus neurofibroma/malignant PNST (MPNST). Higher expression levels (>3+) of MMP-9 were observed in 50% of schwannomas versus none in neurofibromas and MPNSTs, while those of MMP-1 were found in 35.7% of neurofibromas and 66.7% of MPNSTs versus none in schwannomas. RECK was the main inhibitor expressed in these 3 tumors, with no significant differences.
4) Epithelioid sarcoma (ES) cell lines showed that they express emmprin, and co-culture of these ES cells with dermal fibroblasts resulted in upregulation of gelatinase A (MMP-2) in fibroblasts. This stimulation was inhibited by an activity-blocking peptide against emmprin and by antiemmprin antibody. Immunohistochemical analysis of 5 ES patient cases demonstrated diffuse emmprin expression in ES cells and MMP-2 expression in both ES cells and peritumoral fibroblasts. Soluble full-length emmprin released from ES cells was shown to stimulate MMP-2 production by fibroblasts. In conclusion, emmprin is expressed in ES in both membrane and soluble forms and stimulates MMP-2 production via interactions with fibroblasts, which could play a role in ES cell stromal invasion and vascular involvement. Less
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