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Satoru Shintani

Publications and source records attributed to Satoru Shintani.

At least 19 recordsLinked to original sources
PubMed2006

Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells.

Hypoxia increases the invasive and metastatic potential of tumor cells. Increased expression of c-Met/hepatocyte growth factor (HGF)-receptor protein in response to hypoxia in thyroid papillary carcinomas is hypoxia-inducible factor-1 (HIF-1) dependent. Both HGF and c-Met are expressed in human salivary gland cancers. In the current study, we tested whether c-Met expression was regulated by hypoxia and HIF-1alpha using two human salivary gland cancer cell lines: GFP-ACC2 and GFP-ACCM. Hypoxia enhanced the expression of HIF-1alpha in both cell lines, whereas c-Met was markedly induced only in the GFP-ACCM cells, which have metastatic potential. In the latter, hypoxia also promoted HGF-induced invasiveness. Synthetic small-interfering RNA specific for HIF-1alpha inhibited HIF-1alpha expression in the GFP-ACCM cells, and also suppressed the increase in c-Met expression and HGF-induced invasiveness under hypoxic conditions. These results suggest that hypoxia activates the HGF/c-Met system via HIF-1alpha in human salivary gland cancers and might be involved in their metastasis.

Cell Hypoxia↗
PubMed2006

Loss of p12CDK2-AP1 expression in human oral squamous cell carcinoma with disrupted transforming growth factor-beta-Smad signaling pathway.

We examined correlations between TGF-beta1, TbetaR-I and TbetaR-II, p12(CDK2-AP1), p21(WAF1), p27(KIP1), Smad2, and p-Smad2 in 125 cases of human oral squamous cell carcinoma (OSCC) to test the hypothesis that resistance to TGF-beta1-induced growth suppression is due to the disruption of its signaling pathway as a consequence of reduced or lost p12(CDK2-AP1). Immunoreactivity for TbetaR-II decreased in OSCC with increasing disease aggressiveness; however, no differences were observed for TbetaR-I and TGF-beta1. The expression of TbetaR-II significantly correlated with p12(CDK2-AP1) and p27(KIP1) (P < .001 and P < .01, respectively). Furthermore, there was a significant relationship between TbetaR-II expression and p-Smad2 (P < .001). The in vivo correlation of the levels of TbetaR-II, p12(CDK2-AP1), and p27(KIP1) was confirmed in normal and OSCC cell lines. Additionally, in vitro analysis of TGF-beta1-treated cells showed that TGF-beta1 treatment of normal keratinocytes suppressed cell growth with upregulation of p-Smad2, p12(CDK2-AP1), and p21(WAF1) expression, whereas there was no effect on OSCC cell lines. These results provide evidence of a link between a disrupted TGF-beta-Smad signaling pathway and loss of induction of cell cycle-inhibitory proteins, especially p12(CDK2-AP1) in OSCC, which may lead to the resistance of TGF-beta1 growth-inhibitory effect on OSCC.

Aged↗
PubMed2006

[Clinical trial of chemotherapy identified according to chemosensitivity assay for oral cancer patients with unresectable recurrent lesions].

Treatment of patients with unresectable recurrent oral cancer is quite difficult. In particular,there is no scientific evidence to select anti-cancer drugs for patients who were given previous radiation therapy. To select optional chemotherapy regimens, we have employed a new chemosensitivity testing method, a collagen gel droplet embedded culture sensitivity test (CD-DST) for patients with unresectable oral cancer. Six oral cancer patients with recurrence and/or metastatic disease were treated with the optional chemotherapy based on the results of CD-DST. No result was obtained due to a problem of poor growth of tumor cells in one case. In another case, we could not find a sensitive anti-cancer drug among the agents we examined. These 2 patients were treated with selected palliative pain control therapy. Optional chemotherapy based on the results of CD-DST was given to 4 patients showing sensitivity to the anti-cancer drugs examined. Tumor recession or tumor dormancy was observed clinically during a definite period. Toxicity was mild and the median survival was 10.9 months. We therefore conclude that the examination with CD-DST may provide important scientific evidence to determine a suitable chemotherapy for patients with advanced oral cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Effects of apatite foam combined with platelet-rich plasma on regeneration of bone defects.

The objective of this study was to investigate the regenerative effects of apatite foam (AF) combined with platelet-rich plasma (PRP) on bone defects. Critical-sized defects in the tibia of rats were filled with randomly distributed combinations of AF with and without PRP. The animals were killed after three, six, and 12 weeks, and their tissue responses were histologically examined. At three weeks, we found no significant differences in bone regeneration against control group (21.9 +/- 3.1%) when PRP (20.3 +/- 4.2%) and AF (21.6 +/- 2.9%) were used independently of each other. In contrast, significantly (p<0.01) larger amount of bone (32.3 +/- 6.5%) was formed when the defect was filled with PRP-incorporated AF. At six weeks, both PRP (38.1 +/- 3.2%) and AF (39.6 +/- 7.8%) showed significantly (p<0.05) higher rates of bone regeneration than the control, even though they were used independently. Moreover, the amount of regenerated bone significantly (p<0.01) increased in the defect filled with PRP-incorporated AF (76.1 +/- 8.2%). We concluded, therefore, that the combination of PRP and AF may be useful for the regeneration of defected bone.

Animals↗
PubMed2006

CXCR4 expression is associated with lymph-node metastasis of oral squamous cell carcinoma.

The support mechanisms that are involved in lymph-node metastasis of oral squamous cell carcinoma (OSCC) remain largely unknown. Recent studies have demonstrated that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. In this study, we examined the expression and function of chemokines and their receptors in OSCC. The expression of chemokine receptors was assessed in eight OSCC cell lines. CXCR3 mRNA and protein were expressed in all the OSCC cell lines examined, while CXCR4 mRNA and protein were expressed only in HSC2, HSC3, and Ca9-22 cells. Treatment with the ligand for CXCR4, stromal cell-derived factor-1 (SDF-1), enhanced the motility and invasiveness of OSCC cells expressing CXCR4. However, the CXCR3 ligand, Mig, did not affect the migration or invasiveness of CXCR3-positive cells. We also evaluated the clinical significance of CXCR4 expression immunohistochemically. CXCR4 expression was detected in 27 (30%) of the 90 OSCC tissues tested, and was localized in the membrane and cytoplasm of cancer cells. There was a highly significant correlation between CXCR4 expression and lymph-node metastasis (P=0.0035). Collectively, these findings suggest that CXCR4 might be involved in the lymph-node metastasis of OSCC.

Carcinoma, Squamous Cell↗
PubMed2005

CD151 forms a functional complex with c-Met in human salivary gland cancer cells.

In this study, we have attempted to elucidate the expression and function of CD151 in human salivary gland cancer cells. CD151 expression was detected in Acc2 and AccM cells, but not in normal tissues and primary cultured epithelial cells derived from human salivary gland. CD151 has been found to function as a molecular linker in the formation of complexes between c-Met/hepatocyte growth factor (HGF) receptor and integrin alpha3/alpha6. Knockdown of CD151 or integrin alpha3/alpha6 expression almost completely abrogated HGF-stimulated cell growth and migration. In contrast, forced expression of CD151 in Acc2 cells resulted in the increase of the HGF-dependent biological effects. These results suggest that CD151 forms a structural and functional complex with c-Met and integrin alpha3/alpha6, and exerts its oncogenic functions through excessive activation of the HGF/c-Met signalling pathway.

Antigens, CD↗
PubMed2005

Anti-tumor effect of radiation response by combined treatment with angiogenesis inhibitor, TNP-470, in oral squamous cell carcinoma.

Blocking angiogenesis may enhance conventional anticancer treatments such as radiation therapy. In this study, we examined the effects of the angiogenesis inhibitor TNP-470 on human OSCC cell lines HSC2 and KB, with combining radiation therapy in the nude mouse. We evaluated cell-induced neovascularization with dorsal air sac assay, and selected two cells (HSC2: low, KB: high) with different level of cell-induced angiogenesis. The angiogenesis inhibitor TNP-470 was given 30 mg/kg s.c. daily on day 1-5, and irradiation, 8 Gy x 1, was administered on day 1 each week for 3 weeks. Significant inhibition of tumor growth relative to untreated controls was achieved in KB cells showing high induced angiogenesis with both TNP-470 (P < 0.01) and radiation (P < 0.01) and combining TNP-470 and radiation (P < 0.01). We saw little effect of TNP-470 either alone or in addition to the effect of radiation on the HSC2 cells showing low induced angiogenesis. These results suggested that TNP-470 significantly enhanced the effect of radiation on the cells with high neovascularization. These findings indicated that individual evaluation of each tumor neovascularization potential will be important before deciding the anti-angiogenesis treatment.

Angiogenesis Inhibitors↗
PubMed2004

Cyclin G2 dysregulation in human oral cancer.

Using expression microarray, we have previously shown that human cyclin G2 (hCG2) is significantly down-regulated in laser capture microdissected oral cancer epithelia. Western analysis showed detectable hCG2 protein in normal (2 of 2) but not in malignant (4 of 4) oral keratinocyte cell lines. Immunohistochemistry analysis done on oral cancers showed that normal oral mucosa (100%, 12 of 12) and 69.1% (47 of 68) of dysplastic oral epithelia expressed readily detectable hCG2 in the nuclei. However, only 11.1% of oral cancer epithelia (14 of 126) showed mild hCG2 nuclear staining. Interestingly, of the oral cancers devoid of nuclear hCG2 (112 cases), 58 cases (52%) showed cytoplasmic hCG2 immunostaining, whereas the other 54 cases (48%) exhibited neither nuclear nor cytoplasmic hCG2 staining. In vitro functional study by ectopic restoration of hCG2 expression in the human malignant squamous cell carcinoma (SCC) line SCC15 resulted in a significant inhibition of cellular proliferation (P < 0.001) and colony formation (P < 2 x 10(-5)) with increased population of G(1) phase and decreased in S phase (P < 0.01). Furthermore, stable down-regulation of hCG2 by short interference RNA-based gene silencing in immortalized normal oral keratinocytes resulted in enhanced cell growth with increase in S and prominently in G(2) phase. Because hCG2 has been implicated as a negative regulator in cell cycle progression, our results support that hCG2 dysregulation may play an important role in epithelial transformation and the early stages of human oral cancer development.

Animals↗
PubMed2004

Overexpression of cyclooxygenase-2 is associated with radioresistance in oral squamous cell carcinoma.

Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, is overexpressed in many types of malignant tumors, which in turn may stimulate tumor growth and protect against damage by irradiation or cytotoxic agents. The purpose of this study is to investigate the relationship between the radiation sensitivity and elevated level of COX-2. Radiation sensitivity of the eight oral SCC cell lines differed greatly in their response to radiation. Further, the level of the COX-2 expression correlated inversely with increased tumor radiation sensitivity. The similar significant association between the response to preoperative radiation therapy and COX-2 overexpression was observed in the oral SCC patients. In addition, treatment with a COX-2 selective inhibitor enhanced the radioresponse of HSC-2 cell, which constitutively expressed COX-2. These results suggested that COX-2 expression level correlates to radiation tolerance and the COX-2 selective inhibitor may be a potent enhancer for tumor radioresponse in oral SCC.

Adult↗
PubMed2004

Phenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22R.

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth.

Androgens↗
PubMed2004

Expression of vascular endothelial growth factor A, B, C, and D in oral squamous cell carcinoma.

Vascular endothelial growth factor (VEGF) A is known to play an important role in tumor angiogenesis. The additional members of the VEGF family, VEGF B, C and D have been discovered. VEGF C and D show some selectivity toward lymphatic endothelial cells. However, whether VEGF family members play a role in tumor angiogenesis and lymph node metastasis is largely unknown. The aim of the present study was to explore the role of VEGF family members in oral squamous cell carcinoma (OSCC). We evaluated the expression of VEGF family members by immunohistochemistry, reverse transcription-polymerase chain reaction, and western blotting. All VEGF members were expressed at different levels in OSCC. Immunohistological analysis of VEGF family members expression and microvessel density revealed a correlation between VEGF A and B expression and tumor angiogenesis. Although VEGF A and B expression were detected in both node-positive and node-negative OSCC, VEGF C and D expression was detected frequently in node-positive tumors compared to node-negative tumors. These findings suggest a possible relationship between the expression level of VEGF C and/or D and development of lymphatic tumor spread.

Adult↗
PubMed2004

Gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, up-regulates p27KIP1 and induces G1 arrest in oral squamous cell carcinoma cell lines.

High expression of epidermal growth factor receptor (EGFR) is frequently observed in many solid tumor types including oral squamous cell carcinomas (OSCC). Recently, the results of preclinical studies and early clinical trials targeting the EGFR have shown evidence of the activity. In this study, gefitinib ('Iressa', ZD1839), an EGFR-tyrosine kinase inhibitor, inhibited cell proliferation and upregulated p27KIP1 in OSCC cells. Growth inhibition was observed in OSCC xenografts when mice were treated with gefitinib in vivo. A flow cytometric analysis demonstrated that treatment with gefitinib induced accumulation in G1 phase, accompanied by a decrease in the percentage of cells in S phase. Apoptosis was not seen in this study. Cell growth was inhibited by an increase of the cell cycle inhibitor p27KIP1 and a decrease of its ubiquitin ligase subunit Skp2.

Animals↗
PubMed2004

Growth-regulated oncogene-1 expression is associated with angiogenesis and lymph node metastasis in human oral cancer.

Growth-regulated oncogene-1 (GRO-1) is an autocrine growth factor in melanoma and is a member of the CXC family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC receptor 2. A previous article noted that GRO-1 was upregulated in oral cancer using a genome-wide microarray approach. We have examined the expression of GRO-1 in 9 oral squamous cell carcinoma (OSCC) cell lines and 94 OSCC specimens. Using real-time quantitative polymerase chain reaction analyses, GRO-1 expressions were varied in OSCC cell lines. Of the 94 OSCC specimens, 37 (39.4%) showed GRO-1 cytoplasmic immunostaining, and microvessel density revealed a correlation between GRO-1 expression and tumor angiogenesis. GRO-1 expression was also associated with leukocyte infiltration, and lymph node metastasis. These findings suggest a possible relationship between the expression level of GRO-1 and tumor progression.

Aged↗
PubMed2004

Basic and clinical studies on quantitative analysis of lymph node micrometastasis in oral cancer.

Metastasis to cervical lymph nodes (LN) is significantly associated with the outcome of patients with oral cancer. To provide a useful method for the detection of micrometastases, we analyzed 115 LNs from 10 patients with oral cancer using real-time quantitative polymerase chain reaction (PCR) based on the expression of squamous cell carcinoma antigen (SCCA) and cytokeratin 13 (CK13). The sensitivity and quantification of this method were assessed by means of limited dilution of cultured oral cancer cells and a model of cervical LN-metastasis established by inoculating green fluorescent protein (GFP)-expressing cells into the tongue of nude mice. In both investigations, a few cancer cells were detected by real-time quantitative PCR, but not by conventional reverse transcription-PCR (RT-PCR). SCCA mRNA was detected at high levels in metastatic LNs. In contrast, 26 of the 30 control cervical LNs did not express the gene at all, and the rest showed fairly low levels. Of 108 histologically metastasis-negative LNs, 19 (17.6%) expressed SCCA mRNA levels higher than the cut-off value (1.0: mean expression of control LNs + 2SD). CK13 mRNA is not a suitable marker for the real-time PCR since it was detected frequently even in the control LNs. These findings suggest that genetic diagnosis by real-time quantitative PCR based on SCCA mRNA expression may be clinically useful for detecting occult tumor cells in cervical LNs.

Animals↗
PubMed2004

[A case of advanced maxillary carcinoma with cervical lymph node metastases showing a complete response to the combination therapy of CDDP, TS-1 and radiation].

We report a case of right maxillary carcinoma with metastases to the cervical lymph nodes (T4N2cM0, Stage IV). A 76-year-old woman was administered preoperative chemoradiotherapy, followed by curative surgery. TS-1 (80 mg/day), CDDP (5 mg/m2/day) and concurrent radiation (total 40 Gy) induced a complete response. Grade 2 neutropenia, thrombocytopenia and stomatitis were observed. In the primary tumor and cervical metastatic lymph nodes, no viable carcinoma cells were detected and cancer nests were replaced with marked fibrous tissue.

Aged↗
PubMed2004

High frequency methylation of p16INK4A gene during 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.

The p16INK4A tumor suppressor gene can be inactivated by hypermethylation of the promoter region in many type of tumors including oral cancer. We recently studied the relationship of inactivation of p16INK4A and tumorigenesis in oral cancer. The aim of the present study was to describe the relationship between macroscopic changes of rat oral mucosa treated with 4-nitroquinoline 1-oxide (4NQO) and an inactivation of p16INK4A. We analyzed the relation of p16INK4A inactivation by hypermethylation of the promoter region of p16INK4A gene using polymerase chain reaction (PCR), PCR-single-strand confirmation polymorphism (PCR-SSCP), and methylation-specific-PCR (MSP). We observed that methylation of p16INK4A genes were rare in mild and moderate dysplasia, but inactivation was observed at high frequency even in severe dysplasia and SCCs in rat carcinogenesis. The expression pattern of p16INK4A protein, detected by western blotting and immunohistochemistry, were similar to the hypermethylation status of the p16INK4A promoter region. Inactivation by hypermethylation of the promoter region of p16INK4A gene was related to carcinogenesis of oral cancer.

4-Nitroquinoline-1-oxide↗
PubMed2004

Constitutive activation of Stat3 correlates with increased expression of the c-Met/HGF receptor in oral squamous cell carcinoma.

Stat3 belongs to a family of signal transducers and activators of transcription. Constitutive activation of Stat3 has been observed in many human malignancies. In addition, mutated Stat3 has been shown to possess oncogenic potential on its own, and activation of Stat3 signaling is required for HGF/c-Met-mediated tumorigenesis. In this study, we examined the correlation between Stat3 activation and HGF/c-Met signaling in samples of oral squamous cell carcinoma (OSCC). Immunohistochemical examination revealed the phosphorylated form of Stat3 in the nuclei of 62/84 OSCC tissue samples but not in normal mucosa, while c-Met expression was detected in 48 samples. Approximately half of the c-Met positive samples also contained phospho-Stat3. There were highly significant correlations between activation of Stat3 and c-Met expression (p=0.00097) and tumor stage. These results indicate that activation of Stat3 mediated by c-Met is frequently associated with the progression of OSCC.

Adult↗