Int J Stomatol

Int J Stomatol ›› 2021, Vol. 48 ›› Issue (5): 570-578.doi: 10.7518/gjkq.2021064

• Reviews • Previous Articles     Next Articles

Diagnosis and treatment of ameloblastoma from molecular biology perspective

Qian Ying1(),Gong Jiaxing1,Yu Mengfei1,Liu Yu1,Wei Dong2,Zhu Ziyu1,Lu Kejie1,Wang Huiming1()   

  1. 1. Dept. of Oral Implantology, The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310006, China
    2. Dept. of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
  • Received:2020-12-22 Revised:2021-04-12 Online:2021-09-01 Published:2021-09-10
  • Contact: Huiming Wang E-mail:zdqianying@zju.edu.cn;whmwhm@zju.edu.cn
  • Supported by:
    National Key Research and Development Program of China(2018YFA0703000);National Natural Science Foundation of China(81670972);Key Research and Development Program of Zhejiang, China(2017C-01054);Key Research and Development Program of Zhejiang, China(2018C03062);Key Research and Development Program of Zhejiang, China(2017C01063);Post-doctoral Science Foundation of China(2020TQ0257);Post-doctoral Science Foundation of China(2020M681896)

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Abstract:

Ameloblastoma is the most common odontogenic tumor. It is prone to relapse and malignant transformation, and it should be a borderline tumor. To date, several special markers for ameloblastoma have been found. Although the tissue source and pathogenesis of ameloblastoma are not entirely clear, numerous signal transduction pathways have been found closely associated with its occurrence, such as the mitogen-activated protein kinase signaling pathway, Sonic Hedgehog signaling pathway, and canonical WNT/β-catenin signaling pathway. Recently, multiple mutant genes have been found in ameloblastoma, including V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, rat sarcoma viral oncogene homolog (RAS) mutations, and smoothened (SMO) mutations. Different mutant ameloblastomas have different clinical characte-ristics and biological behavior. The histological characteristics of ameloblastomas can guide typing, and they have distinguished significance for treatment and prognosis. This review will focus on classification, molecular level markers, pathogenesis, targeted therapy, and prognosis of ameloblastoma to explore clinically relevant genotype-phenotype correlations and assist future diagnosis and treatment.

Key words: ameloblastoma, gene mutation, mitogen-activated protein kinase signaling pathway, Sonic Hedgehog signaling pathway, targeted therapy

CLC Number: 

  • R739.81

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Tab 1

Classification and characteristics of ameloblastoma markers"

分类 标志物 特点
反映细胞表面
和细胞内变化
的标志物		 B淋巴细胞瘤-2（B-cell lymphoma-2,BCL-2） BCL-2是一种重要的抗凋亡蛋白,参与细胞增殖与凋亡[13]。有研究[13]显示：BCL-2通过作用SHH通路的下游靶点,起到促进肿瘤细胞存活的作用。有学者[14]发现：BCL-2蛋白在成釉细胞瘤细胞外层表达,而在成釉细胞瘤细胞内层（星网状细胞和鳞状细胞）不表达;caspase-3等促凋亡蛋白主要在肿瘤岛中心的鳞状细胞及颗粒状细胞中表达。这表明成釉细胞瘤具有2种相对明显的模式,一种是在肿瘤岛周围层中的抗凋亡增殖位点,另一种是在肿瘤岛中心中的促凋亡位点
E-钙黏蛋白（E-cadherin）和β-catenin E-cadherin是一种与成釉细胞瘤侵袭性相关的跨膜上皮细胞黏附蛋白,对维持上皮细胞完整性至关重要[15]。E-cadherin与β-catenin有关,其中β-catenin的功能直接受WNT/β-catenin信号通路调控。当该通路处于静息状态时,β-catenin位于细胞膜中,与E-cadherin一起在细胞黏附中发挥重要作用。当该通路被激活时,β-catenin转移到细胞核中并形成一个转录因子,在成釉细胞瘤的发展、侵袭和转移过程中充当转录介质[16]
基质金属蛋白酶（matrix metalloproteina-ses,MMP） MMP在成釉细胞瘤的细胞增殖、侵袭和骨吸收中发挥重要作用[17]。MMP-2和MMP-9是WNT/β-catenin信号通路的蛋白水解酶,可降解细胞外基质蛋白,与成釉细胞瘤的局部侵袭性有关[18,19]。MMP-9不仅来自成釉细胞瘤细胞,也可由破骨细胞分泌,破骨细胞可以降解骨的细胞外基质,可能与成釉细胞瘤骨侵袭相关[19]
细胞增殖标志物 核相关抗原Ki-67（nuclear related antigen Ki-67,Ki-67）和增殖细胞核抗原（prolife-rating cell nuclear antigen,PCNA） Ki-67和PCNA均是评估成釉细胞瘤细胞增殖潜能的指标。Ki-67蛋白存在于细胞周期的所有活跃阶段（G1、S、G2和有丝分裂期）,但在静息细胞（G0）中不存在,这一特点使其作为肿瘤标志物在临床病理诊断中被广泛应用[20,21,22]。PCNA是脱氧核糖核酸（deoxyribonucleic acid,DNA）合成和修复的重要蛋白,在G1/S期升高,在细胞增殖的启动上起重要作用。研究[21]显示：Ki-67的表达量在不同类型成釉细胞瘤之间存在显著差异。促结缔组织增生型成釉细胞瘤是增殖指数（以阳性细胞的百分比表示）最低的肿瘤;外周型和实性/单囊型成釉细胞瘤的Ki-67阳性率相似,但各亚型间存在一定差异。因此,笔者推测：不同类型上皮细胞的比例以及外周型和实性/单囊型成釉细胞瘤的不同生长机制可能影响增殖指数的结果。研究者[21,22]使用PCNA抗体进一步检测不同类型成釉细胞瘤的增殖指数,结果显示：不同亚型的成釉细胞瘤中,PCNA的表达量无显著性差异,因此认为Ki-67是一种比PCNA更敏感和特异的成釉细胞肿瘤增殖标志物
肿瘤血管生成
相关标志物		 血管内皮生长因子（vascular endothelial growth factor,VEGF） VEGF的表达水平与成釉细胞瘤的状态和预后相关[23,24]。VEGF具有增加血管通透性、促进血管内皮细胞增生和血管生成的作用,其作为牙源性囊肿上皮细胞和肿瘤上皮细胞的有丝分裂因子,可通过自分泌在上皮细胞增殖中发挥作用[23]。有研究[24]在良恶性成釉细胞瘤中均检测到VEGF的高表达,提示牙源性上皮细胞高表达VEGF可能与肿瘤样改变以及恶性转化有关。有学者[4]认为：WNT/β-catenin信号通路的异常激活可能导致成釉细胞瘤中VEGF表达上升
肿瘤恶化相关
标志物		 钙黄体素 钙黄体素是成釉细胞瘤的特异性免疫组织化学标志物,在单囊型、实性/多囊型成釉细胞瘤中的表达阳性,可作为这2种类型的成釉细胞瘤和其他牙源性肿瘤鉴别诊断的重要辅助手段[25]。钙黄体素是一种在成牙过程中由成釉细胞分泌的钙结合蛋白,其确切生物学功能尚不清楚,可能参与细胞增殖和分化,与成釉细胞瘤的侵袭性相关,是恶性成釉细胞瘤相关的免疫组织化学标志物[26]

Fig 1

Signal pathways and targeted therapeutic drugs associated with ameloblastoma"

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