Molecular pathological study of mechanism in malignant changes of oral benign tumors

本研究旨在探讨口腔良性肿瘤恶变的分子机制。我们主要集中在涎腺多形性腺瘤，因为我们已经提出了多形性腺瘤内不典型肿瘤细胞恶变或局灶性癌的可能性。为此，我们从一位61岁女性的腮腺良性多形性腺瘤中分离出六个细胞系统(命名为SMAP1至SMAP6)。SMAP1/3表现为多角形细胞的导管上皮特征，SMAP4/6呈梭形，有一定的肌上皮细胞分化。染色体分析表明，该细胞不仅存在5N倍体等数目异常，平均107条染色体，而且还存在各种结构异常，如缺失、易位、衍生和等着丝粒染色体。其中，der(9)t(9；13)(p13.3；q12.3)在所有6个细胞系统中都是共有的。此外，它们都是…More有p53基因第249密码子最后一个碱基G(AGG至AG_)的共同缺失，导致其无意义基因产物的产生。结果提示，多形性腺瘤含有癌前病变的肿瘤细胞，并可通过上述基因改变转化为恶性细胞，本研究首次在体外证实了涎腺腺瘤可继发癌变。包膜侵犯和血管侵犯。对104例手术标本进行组织病理学检查，其发生率分别为100%(囊外20%)和15%。在有包膜或血管侵犯的部位，间质呈粘液样，血管化较差。这种组织学可以用低氧相关的血管内皮生长因子和缺氧诱导因子-1a的表达模式来解释。从婴儿期黑色素性神经外胚层肿瘤建立的细胞中，发现了与SMAP细胞相同的染色体改变，这种易位值得进一步研究，以探讨良性肿瘤继发性恶变的分子机制。较少

This research project was carried out in order to study a possible molecular pathway of malignant transformation of oral benign tumors. We mainly focus on salivary pleomorphic adenoma, because we had already proposed a possibility of malignant changes of atypical tumor cells or focal carcinomas within pleomorphic adenomas. To this end, we have isolated six cell systems (designated SMAP1 to SMAP6) from a benign pleomorphic adenoma of the parotid gland of a 61 year-old female. SMAP1/3 showed duct epithelial characteristics with polygonal cell shapes, while SMAP4/6 were spindle-shaped with some myoepithelial cell differentiation. Chromosome analyses showed the cells had not only numeral abnormalities such as 5n ploidies with average numbers of 107 chromosomes but also various kinds of structural abnormalities, such as deletions, translocations, derivatives and isodicentric chromosomes. Among them, der(9)t(9; 13)(p13.3;q12.3) was shared by all of the six cell systems. In addition, they all … More had a common deletion of the last base G of codon 249 (AGG to AG_) of the p53 gene, which would result in generation of its nonsense gene product. The findings suggest that pleomorphic adenoma contains tumor cells which are precancerous and are able to transform into malignant with above mentioned gene alterations, and the present study is the first in-vitro demonstration that carcinomas can arise secondarily from adenomas in the salivary gland.In addition to such gene alterations, there were some other biological characteristics to pleomorphic adenomas. They were capsular and vascular invasions. Their frequency was 100% (extracapular 20%) and 15%, respectively, when examined histopathologically in 104 surgical specimens. In the sites with capsular or vascular invasions, the stroma was myxoid and poorly vascularized. This histology was explained by VEGF and HIF-1a expression modes, which were hypoxia-related. In cells established from a melanotic neuroectodermal tumor of infancy, there was the same chromosome alteration found in SMAP cells, and this translocation will be worthwhile to be investigated further for the molecular mechanism of secondary malignant changes of benign tumors. Less