Accurate assessment of malignancy in oral squamous cell carcinoma is essential to optimize treatment planning. To detect a biomarker related to malignant propensity in gingival squamous cell carcinoma (GSCC), quantitative gene expression analysis of tetraspanin family genes was conducted. In 73 cases of GSCC, total RNA was extracted from carcinoma tissues, and gene expression was analyzed by quantitative real time-PCR. Six tetraspanin family genes (CD9, CD63, CD81, CD82, CD151, NAG-2) were investigated. Housekeeping genes (ACTB and GAPDH), anchor protein genes (JUP and PXN) and an integrin gene (ITGA3) were used as reference genes. Forty-five gene expression ratios were calculated from these 11 gene expression levels and were analyzed with clinical parameters using multivariate statistical methods. According to the results of the logistic regression analysis subjecting cervical lymph node metastasis as a target variable, CD9/ACTB (p 5 0.013) or CD9/CD82 (p 5 0.013) in addition to tumor size (p 5 0.028) were detected as significant factors. In Cox proportional hazards regression analysis, delayed cervical lymph node metastasis (p 5 0.039) and tumor cell positive surgical margin (p 5 0.032) in addition to CD151/GAPDH (p 5 0.024) were detected as significant factors for death outcome. A Kaplan-Meier survival curve presented a significantly lower survival rate of the group with a CD151/GAPDH value of 10 or more (log rank and generalized Wilcoxon tests: p 5 0.0003). Results of this study present the usefulness of CD9 and CD151 expression levels as biomarkers for assessment of malignancy in GSCC. They also indicate that detection of residual tumor cells at the surgical margin and the biological malignancy of a tumor interdependently affects prognosis. ' 2009 UICC Key words: biomarker; tetraspanin; CD9; CD82; CD151; gingival squamous cell carcinoma; lymph node metastasis; death outcomeThe incidence of squamous cell carcinoma (SCC) arising from gingiva is relatively high among oral malignant neoplasms, and approximately half of the cases also presented with cervical lymph node (LN) metastasis. Because gingival SCC (GSCC) easily invades the jawbone and its surrounding tissues such as nerve, muscles, the nasal cavity and skin, determination of the extent of resection and reconstruction are significant issues in treatment of advanced cases.1-3 Therefore, determination of optimal treatment plans based on accurate assessment of biological malignancy is extremely important not only in terms of controlling cancers but also for minimizing dysfunction after treatment. Candidates for biomarkers of head and neck cancers including oral SCC (OSCC) were found in some studies; however, they have not been of practical use. 4,5 Although diagnostic imaging, status of lymph node metastasis and histology still will be clinically essential criteria, they are not able to provide sufficient information to realize the individualized treatment of OSCC in the future. A precise malignancy diagnosis of OSCC, such as prediction of potential metast...
We have histologically examined vascular invasion and calcification of the hypertrophic zone during endochondral ossification in matrix metalloproteinase (MMP)-9 deficient (MMP-9 −/− ) mice and in their littermates at 3 days, 3 weeks and 6 weeks after birth. Capillaries and osteoclasts at the chondro-osseous junction showed an intense MMP-9 immunopositivity, suggesting that they recognize chemical properties of cartilaginous matrices, and then release MMP-9 for cartilage degradation. CD31-positive capillaries and tartrate-resistant acid phosphatase-reactive osteoclasts could be found in the close proximity in the region of chondro-osseous junction in MMP-9 −/− mice, while in wild-type mice, vascular invasion preceded osteoclastic migration into the epiphyseal cartilage. Although MMP-9 −/− mice revealed larger hypertrophic zones, the index of calcified area was significantly smaller in MMP-9 −/− mice. Interestingly, the lower layer of the MMP-9 −/− hypertrophic zone showed intense MMP-13 staining, which could not be observed in wild-type mice. This indicates that MMP-13 may compensate for MMP-9 deficiency at that specific region, but not to a point at which the deficiency could be completely rescued. In conclusion, it seems that MMP-9 is the optimal enzyme for cartilage degradation during endochondral ossification by controlling vascular invasion and subsequent osteoclastic migration.Endochondral ossification enables the longitudinal growth of long bones, keeping the balance between chondrocyte proliferation and differentiation (i.e., appositional and interstitial growth) and vascular invasion into cartilage prior to bone deposition (12,27). The length of the hypertrophic zone appears to be maintained by two mechanisms: 1) the rate at which chondrocytes enter the hypertrophic phenotype and 2) the pace at which vascular endothelial cells invade the hypertrophic zone of the cartilage. After the formation of calcified cartilage matrices, the process of endochondral ossification involves a well-defined series of events in which osteogenic and osteoclastic cells replace calcified cartilage for bone (2). At an erosion zone, vascular endothelial cells invade and collapse incompletely-calcified transverse partitions of cartilage matrix, making a way for osteoclastic and osteoblastic migration. On the other hand, the longitudinal intercolumnar septae are
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