Natsuyo Noguchi

SIGNIFICANCE OF STROMAL DESMOPLASIA AND MYOFIBROBLAST APPEARANCE AT THE INVASIVE FRONT IN SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY

Tumor invasion involves complex interactions between tumor and stromal cells. We examined the extent of connective tissue in the tumor stroma and whether myofibroblasts play a role in assisting cancer invasion and metastasis.

Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma.

Development of a new therapeutic approach to improve the prognosis of high grade invasion of oral squamous cell carcinoma is needed. To elucidate the effect of a fibroblast inhibitor (tranilast), we investigated the proliferation and metastasis of oral squamous cell carcinoma in a mouse model. The effect of tranilast on tumour growth, lymph node metastases, microvessel density, and the proliferating cell nuclear antigen (PCNA) labelling index of oral squamous cell carcinoma implanted into the tongue of nude mice was evaluated. Tumour growth and the incidence of cervical lymph node metastases were significantly suppressed by the administration of tranilast. The amount of fibrous tissue, the microvessel density, and the PCNA labelling index of tumour were also significantly reduced. Administration of a fibroblast inhibitor may well be clinically effective for the treatment of oral squamous cell carcinoma.

Expression form of p53 and PCNA at the invasive front in oral squamous cell carcinoma: correlation with clinicopathological features and prognosis.

BACKGROUND  Abnormalities in cell-cycle-controlling genes are important in the malignant transformation and proliferation of tumors. Among these genes, the tumor suppressor gene p53 is the most notable, and its mutations provide an indicator of tumor progression and prognosis. Proliferating cell nuclear antigen (PCNA) is a highly conserved nuclear protein that is expressed during cell replication and DNA repair. This study examined the expression of p53 and PCNA at the invasive front of oral squamous cell carcinomas (OSCC) by immunohistochemical staining, and investigated the relationship of these proteins to clinicopathological findings and prognosis. METHODS  Fifty-nine biopsy cases of OSCC were examined by immunohistochemical staining. Clinicopathological data were gathered and patient survival was analyzed. RESULTS  The p53 labeling index (p53-LI) and PCNA labeling index (PCNA-LI) were examined at the invasive front of the tumors. A high p53-LI (p53+) was observed in 17 of the 59 cases (28.8%) and a high PCNA-LI (PCNA+) was observed in 28 of the 59 cases (47.5%). Among the modes of cancer invasion, many of the p53+/PCNA+ cases could be confirmed as highly invasive cancer (P < 0.05). In addition, the p53+/PCNA+ cases showed a high risk of tumor recurrence compared with the other expression forms, and patients with p53+/PCNA+ had a worse prognosis than those with the other expression forms. High labeling indices of p53 and PCNA are associated with poor prognosis in patients with OSCC. CONCLUSION  We suggest that it is important to investigate the expression of p53 and PCNA at the invasive front of OSCC.

Prognostic value of vascular endothelial growth factors A and C in oral squamous cell carcinoma

BACKGROUND Vascular endothelial growth factor (VEGF) family members play a major role in angiogenesis and vascularization. VEGF-A promotes tumor angiogenesis by stimulating the growth of tumor vascular endothelial cells. In addition, VEGF-C has been identified as a potent inducer of lymphangiogenesis in tumor and lymph node metastasis. Previous studies have investigated the association between clinicopathological factors and the expression of VEGF-A and VEGF-C in oral squamous cell carcinoma cancer (OSCC), but the results are contradictory. In this study, we investigated the relationship between VEGF-A and VEGF-C expression and OSCC clinicopathological factors and prognosis. METHODS Expression of VEGF-A and VEGF-C was evaluated in surgical specimens from 61 patients with OSCC and three human oral cancer cell lines (OSC-19, OSC-20 and HOC313) by immunohistochemical staining and enzyme-linked immunosorbent assay, respectively. We also determined the relationship between the 5-year survival rate and clinicopathological factors, such as TNM classification (Union for International Cancer Control, UICC), lymph node metastasis, recurrence, histological differentiation, location, and mode of invasion. RESULTS VEGF-A expression correlated significantly with lymph node metastasis. VEGF-C expression was associated with lymph node metastasis, recurrence, and a poorer 5-year survival rate. A multivariate analysis demonstrated that VEGF-C is an independent prognostic factor for patients with OSCC. VEGF-C expression was significantly up-regulated in HOC313 cells compared to OSC-19 and OSC-20 cells. CONCLUSIONS These results indicate that VEGF-C may be a predictive factor for OSCC outcome, lymph node metastasis, and recurrence. Moreover, VEGF-C may be an important factor in the development of new therapies for OSCC patients.

Predictive Value of Measuring p53 Labeling Index at the Invasive Front of Oral Squamous Cell Carcinomas

Many studies have revealed the frequency of p53 abnormalities in oral cancer. However, it reports only on the relation between clinicopathological findings and p53 expression, and there is no study to examine the relation to the p53 labeling index (p53-LI). The purposes of this study were to examine the correlation between p53 labeling index (p53-LI) at the invasive front of oral squamous cell carcinomas (OSCC) and clinicopathological findings by immunohistochemical staining, and to evaluate clinical significance of measuring p53-LI at the invasive front of OSCC. Sixty-six biopsy specimens of OSCC were randomly selected. Patient age, gender, primary sites, T category, N category, degree of differentiation and mode of cancer invasion were analyzed. p53 expression did not correlate significantly with the clinical findings. However, significant differences were found between p53-LI and the degree of cell differentiation (p < 0.05). The p53-LI of high-grade invasive tumors was significantly larger than that of low-grade invasive tumors (p < 0.05). The overall survival rate (OS) among low-scoring p53-LI cases was 75.5% whereas that for high-scoring p53-LI cases was 40.6%. The disease-free survival rate (DFS) among low-scoring p53-LI cases was 39.5% whereas that for high-scoring p53-LI cases was 76.1%. Patients with low-scoring p53-LI had a significantly worse prognosis than those with among high-scoring p53-LI (p < 0.05). Consequently, the measurement of p53-LI at the invasive front of OSCC is significant as one of the indicators of prognosis.

Inhibitory effect of neoadjuvant chemotherapy on metastasis of oral squamous cell carcinoma in a mouse model

The presence or absence of metastasis bears an important influence on the prognosis of head and neck cancer patients. Neoadjuvant chemotherapy has become widely employed as an initial treatment. However, the actual effectiveness of neoadjuvant chemotherapy on metastasis is still unestablished. Therefore, using an orthotopic implantation model in which cervical lymph node metastasis of oral squamous cell carcinoma can be reproduced, we investigated the inhibitory effect of neoadjuvant chemotherapy on metastasis. A highly invasive and metastatic human oral squamous cell carcinoma cell line, OSC-19 cells, was implanted into the tongues of nude mice. After implantation, the mice were divided into four groups: S (surgery), C+S (preoperative chemotherapy+surgery), S+C (surgery+postoperative chemotherapy), and a control (nontreatment) groups. The treatment (tumor resection or chemotherapy) was started 7 days postimplantation. The effects of each treatment on cervical lymph node metastasis were investigated by examining the rate of lymph node metastasis formation at 28 days postimplantation. In the control group, five of the 11 mice died of cachexia before the end of the experiment. However, all mice in the S, C+S, and S+C groups survived until 28 days after implantation. The cervical lymph node metastasis rates were 81.8% in S, 18.1% in C+S, 63.6% in S+C, and 100% in control groups. Thus, metastasis to the cervical lymph node was markedly inhibited by the combination of neoadjuvant chemotherapy and tumor resection. The findings of this study indicate that neoadjuvant chemotherapy is effective for inhibiting metastasis, and that it is necessary to begin chemotherapy as early as possible to achieve an inhibitory effect on metastasis. Considering these effects, if anticancer drugs are used, better therapeutic results can be expected.

Fibroblast Growth Factor-2 Accelerates Invasion of Oral Squamous Cell Carcinoma

Abstract The aim of this study was to examine the effects of fibroblast growth factor-2 (FGF-2) on cancer cell invasion on fibroblast proliferation in an in vitro model of invasion. Three kinds of human oral squamous cell carcinoma cell lines with different invasive activity were used: OSC-20, OSC-19 (lower invasive type), HOC313 (higher invasive type). FGF-2 its high-affinity receptors FGFR-1 FGFR-2 were detected by western blotting. The expression of FGF-2 FGFRs mRNA was examined in cultured human oral squamous cell carcinoma cells by reverse transcriptase polymerase chain reaction (RT-PCR). Furthermore, recombinant human FGF-2 (rhFGF-2) was reacted with each cell line, the invasion rate was determined by invasion assay. We also observed the behavior of cancer cell invasion in the collagen gel invasion model in the presence or absence of FGF-2-neutralizing antibody (anti-FGF-2). HOC313 cells showed higher expression of FGF-2 than OSC-20 OSC-19 cells. The addition of rhFGF-2 promoted not only the proliferation of fibroblasts, but also the invasion of all cancer cell lines. In contrast, the addition of anti-FGF-2 completely inhibited the invasion of OSC-20 OSC-19 cells. These results suggest that a higher invasiveness of squamous carcinoma cells is associated with higher production of FGF-2, which acts in an autocrine fashion to promote cancer cell invasion, in a paracrine fashion to promote fibroblast proliferation.