Lazzereschi D, Mincione G, Coppa A, Ranieri A, Turco A, Baccheschi G, Pelicano S, Colletta G
Dept. of Experimental Medicine and Pathology, Rome, Italy.
J Exp Clin Cancer Res. 1997 Sep;16(3):325-32.
The development of cancer is due to the accumulation of multiple somatic mutations, in some cases following germline mutations, which occur in hereditary malignancies such as retinoblastomas or multiple endocrine neoplasia (MEN 2A and B). Genetic alterations or changes in the expression of growth regulatory genes can lead to the initiation of malignant transformation and to eventual tumor progression. Cells that have undergone these cumulative alterations in either the structure or expression of these regulatory genes generally possess a selective growth and/or metastatic advantage over other normal non-transformed cells. Thus, activation of dominantly transforming oncogenes by point mutations, gene amplification, chromosomal translocation or insertional mutagenesis can lead to uncontrolled cellular growth or to a disruption in normal differentiation or apoptosis. Equally contributory to the process of malignant progression is the inactivation of recessive tumor suppressor genes due to point mutations and/or loss of heterozygosity in one allele, which can ultimately lead to a reduction of homozygosity in both alleles. Thyroid tumors in humans represent a particularly suitable multistage model of epithelial tumorigenesis. In fact, even though most thyroid neoplasms originate from a single cell type, i.e. the thyroid follicular cell, they include a broad spectrum of tumors with different phenotypic characteristics and variable biological and clinical behaviour. Multiple degrees of malignancies have been defined: from the benign colloid adenomas through the slowly progressive differentiated papillary and follicular carcinomas to the invariably fatal anaplastic carcinomas, although these histological changes are not necessarily sequential. In this review an effort has been made to summarize and integrate new data published on genetic lesions and altered expression of genes involved in the tumorigenesis of the follicular type of thyroid cancer. We have focused our interest only on gene alterations inducing gain or loss of function, that have been studied in vivo in human thyroid tumor specimens by the use of different techniques, such as PCR mediated DNA analyses, sequencing, mRNA level evaluation and protein expression by immunohistochemical staining.
癌症的发生是由于多种体细胞突变的积累，在某些情况下是继种系突变之后发生的，种系突变见于视网膜母细胞瘤或多发性内分泌肿瘤（MEN 2A和B）等遗传性恶性肿瘤。生长调节基因的遗传改变或表达变化可导致恶性转化的启动和最终的肿瘤进展。在这些调节基因的结构或表达上经历了这些累积改变的细胞，通常比其他正常未转化细胞具有选择性生长和/或转移优势。因此，点突变、基因扩增、染色体易位或插入诱变导致显性转化癌基因的激活，可导致细胞生长失控或正常分化或凋亡的破坏。隐性肿瘤抑制基因由于点突变和/或一个等位基因的杂合性丧失而失活，这同样对恶性进展过程有作用，最终可导致两个等位基因的纯合性降低。人类甲状腺肿瘤是上皮肿瘤发生的一个特别合适的多阶段模型。事实上，尽管大多数甲状腺肿瘤起源于单一细胞类型，即甲状腺滤泡细胞，但它们包括具有不同表型特征以及可变生物学和临床行为的广泛肿瘤类型。已经定义了多个恶性程度：从良性胶样腺瘤到进展缓慢的分化型乳头状和滤泡状癌，再到 invariably fatal 的未分化癌，尽管这些组织学变化不一定是连续的。在本综述中，我们努力总结并整合了关于滤泡型甲状腺癌肿瘤发生过程中基因损伤和基因表达改变的新数据。我们仅关注诱导功能获得或丧失的基因改变，这些改变已通过不同技术在人类甲状腺肿瘤标本中进行了体内研究，如PCR介导的DNA分析、测序、mRNA水平评估以及免疫组织化学染色检测蛋白质表达。
