国际口腔医学杂志

国际口腔医学杂志 ›› 2021, Vol. 48 ›› Issue (5): 570-578.doi: 10.7518/gjkq.2021064

• 综述 • 上一篇    下一篇

从分子生物学角度对成釉细胞瘤诊断及治疗的考量

钱颖1(),龚佳幸1,俞梦飞1,刘宇1,魏栋2,朱子羽1,陆科杰1,王慧明1()   

  1. 1.浙江大学医学院附属口腔医院口腔种植中心 浙江大学口腔医学院 浙江省口腔生物医学研究重点实验室 杭州 310006
    2.浙江大学医学院附属第一医院口腔颌面外科 杭州 310006
  • 收稿日期:2020-12-22 修回日期:2021-04-12 出版日期:2021-09-01 发布日期:2021-09-10
  • 通讯作者: 王慧明
  • 作者简介:钱颖,硕士,Email： zdqianying@zju.edu.cn
  • 基金资助:
    国家重点研究发展计划(2018YFA0703000);国家自然科学基金(81670972);浙江省重点研究发展计划(2017C-01054);浙江省重点研究发展计划(2018C03062);浙江省重点研究发展计划(2017C01063);中国博士后科学基金(2020TQ0257);中国博士后科学基金(2020M681896)

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
  • 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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摘要：

成釉细胞瘤是较为常见的牙源性肿瘤。它易复发、易恶变,属于临界瘤。成釉细胞瘤具有许多特殊的标志物,虽然目前其组织来源及发病机制尚未明确,但其发生与多种信号转导途径密切相关,包括有丝分裂原活化蛋白激酶（MAPK）信号通路、Sonic Hedgehog（SHH）信号通路和经典WNT/β-catenin信号通路。鼠类肉瘤滤过性毒菌致癌同源体B1（BRAF）突变、大鼠肉瘤病毒致癌基因同源物（RAS）突变和Smoothened（SMO）突变等多种突变基因型已在成釉细胞瘤中被发现,不同突变型的成釉细胞瘤有不同的临床特点和生物学行为,结合组织学特点可用于指导分型,对治疗及预后具有重要意义。为了进一步探讨这种与临床相关的基因型-表型相关性,本文就成釉细胞瘤的分类、分子水平标志物、发病机制、靶向治疗及预后进行综述,以期对今后的诊断和治疗有所帮助。

关键词: 成釉细胞瘤, 基因突变, 有丝分裂原活化蛋白激酶信号通路, Sonic Hedgehog信号通路, 靶向治疗

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

中图分类号: 

  • R739.81

表 1

成釉细胞瘤标志物的分类及特点"

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]

图1

成釉细胞瘤相关信号通路及靶向治疗药物 MAPK信号通路在成釉细胞瘤中被激活,普纳替尼抑制该通路的FGFR2突变,维罗非尼和达拉非尼抑制BRAF突变,曲美替尼抑制MEK/ERK突变;SHH信号通路的激活与成釉细胞瘤的发生有关,环胺、维莫德吉和伊曲康唑抑制SMO突变,三氧化二砷抑制GLI蛋白;WNT/β-catenin信号通路的激活参与成釉细胞瘤的发生,WNT配体与LRP-5/6和Frizzled受体结合,抑制GSK-3β的活性,使β-catenin无法磷酸化并使其在细胞核中聚积,从而激活WNT靶基因表达。"

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