Minoru Kanke

Granulocyte-macrophage colony-stimulating factor upregulates matrix metalloproteinase-2 (MMP-2) and membrane type-1 MMP (MT1-MMP) in human head and neck cancer cells.

Matrix metalloproteinase-2 (MMP-2) and membrane type 1-MMP (MT1-MMP) play an important role in the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC), but the mechanism of their regulation is not clearly understood. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be associated with cancer invasion and metastasis. We hypothesized that GM-CSF may upregulate MMP-2 and/or MT1-MMP expression in HNSCC cells, and may thereby influence their ability to invade and metastasize. We studied the effects of GM-CSF on the production of MMP-2 and MT1-MMP in HNSCC cell lines SAS and HSC-2. Gelatin zymography of conditioned media derived from HNSCC cells revealed a major band of 68 kDa, which was characterized as proMMP-2. GM-CSF stimulated the production of proMMP-2 in both cell lines in a dose-dependent manner. Treatment with 50 ng/ml GM-CSF for 24 h increased the proMMP-2 activity 3.4-fold in SAS cells and 2.3-fold in HSC-2 cells compared with untreated controls. Northern blot analyses demonstrated that GM-CSF led to elevated mRNA levels of MMP-2 and MT1-MMP in both cell lines. The results identify GM-CSF as a regulator of MMP-2 and MT1-MMP expression in certain types of HNSCC, and suggest that GM-CSF may contribute to the invasiveness of HNSCC through the regulation of MMP-2 and MT1-MMP expression.

Clinicopathological Significance of Expression of CD44 Variants in Head and Neck Squamous Cell Carcinoma

Splice variants of the cell surface glycoprotein CD44 have been reported to be associated with the progression of various human tumors. The aim of this study is to determine the correlation between the expression of CD44 isoforms, especially CD44 variant 2 (CD44v2), and the clinicopathological features of head and neck squamous cell carcinomas (HNSCCs). The expression of CD44 isoforms was evaluated immunohistochemically in paraffin‐embedded tissues from 89 primary lesions, using monoclonal antibodies against CD44 standard (CD44st), CD44 variant 6 (CD44v6) and CD44v2. Cancer tissues from 89 (100%), 85 (95.5%) and 59 (66.3%) patients showed positive immunoreactivity for CD44st, CD44v6 and CD44v2, respectively. A significant correlation was observed between the down‐regulation of CD44v2 and poorer differentiation of the tumor cells (P=0.02). We could not find any significant correlation between the expression of CD44v2 and T stage or N stage (lymph node status). However, the rate of positive cervical lymph node metastasis tended to increase with reduced expression of CD44v2 (P=0.08). Down‐regulation of CD44v2 expression was correlated with shorter overall survival (P=0.01). Furthermore, Coxs multivariate analysis revealed that only CD44v2 expression and lymph node status were independent prognostic factors. These findings suggest that down‐regulation of CD44v2 expression may be one of the biological markers for the degree of malignancy in HNSCCs.

Adjuvant Chemotherapy with Oral Tegaful and Uracil for Maxillary Sinus Carcinoma

We have applied tegaful and uracil (UFT) treatment as adjuvant chemotherapy to patients after the completion of primary therapy. UFT was given per os at a dose of 300 or 400 mg/day for more than 1 year. A retrospective study was conducted on 15 patients, assessed as the UFT-treated group, and 24 patients assessed as the UFT-nontreated group. The 5-year survival rate in patients treated or not treated with UFT was 76.6 and 22.6%, respectively. Among those who underwent surgery in combination with other therapy, the 5-year survival rate was 74.1% with UFT and 27.3% without UFT. In patients receiving chemotherapy plus radiotherapy alone, the 5-year survival rate was 80.0% with UFT and 19.2% without UFT. In 23 patients with proven effects of neoadjuvant chemotherapy comprising 18 PR cases and 5 CR cases, a comparison was made between 10 patients treated with UFT and 13 patients not treated with UFT. As a result, the 5-year survival was 76.2 and 17.9%, respectively. In the patients with T3 disease, who occupied the majority, the 5-year survival rate was 71.4 and 23.8%, respectively. Adjuvant chemotherapy with UFT tends to show a substantial significant difference particularly in patients who were successfully treated with radiotherapy plus chemotherapy as the primary treatment. UFT was clearly shown to have a statistically significant effect, despite a small population. The findings of the present investigation point to the value of conducting further study to ascertain the effect of UFT by a randomized trial in a larger population.