第二军医大学  2015, Vol. 36 Issue (4): 373-377   PDF    
肝癌相关的分子信号通路及治疗靶标
吴建锋1, 赵腾2, 曹广文1    
1. 第二军医大学热带医学与公共卫生学系流行病学教研室, 上海 200433;
2. 第二军医大学学员旅5队, 上海 200433
摘要:肝细胞癌是我国最常见的一种原发性肝癌,目前发病原因尚不明确。研究表明,多种细胞信号转导通路的异常活化参与肝癌的发生发展,包括:血管内皮细胞生长因子受体、表皮生长因子受体、血小板衍生生长因子受体、类胰岛素生长因子受体等,这些信号通路的异常活化最终导致细胞增殖、血管形成、侵袭和转移及对凋亡耐受的发生。目前肝癌的治疗方法主要包括药物、手术、放射治疗及生物免疫治疗等,但这些传统治疗方法对肝癌治愈效果不佳,副作用大,随着对肝癌相关信号通路的研究逐步深入,以上述通路为靶点的抗肿瘤治疗为肝癌治疗提供了新的前景。
关键词肝肿瘤     肝细胞癌     信号通路     治疗靶标     表皮生长因子受体     乙型肝炎病毒    
Hepatocellular carcinoma: progress in signaling pathways and therapeutic targets
WU Jian-feng1, ZHAO Teng2, CAO Guang-wen1    
1. Department of Epidemiology, Faculty of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China;
2. The 5th Team of Student Brigade, Second Military Medical University, Shanghai 200433, China
Abstract: Hepatocellular carcinoma is the most commonly-seen primary liver cancer in China, with its etiology still not fully understood. Research has shown that many signaling pathways are involved in the development and progression of liver cancer, including vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, insulin-like growth factors receptor, and so on. The abnormality of these signaling pathways finally leads to cell proliferation, angiogenesis, invasion and metastasis, and apoptosis tolerance. The current treatment of liver cancer mainly includes drugs, surgery, radiation therapy and immune therapy, but there is still an urgent needs for more effective treatment with less adverse effect. It is hoped that with the progression in the signal pathways of hepatic cancer, anti-tumor treatments with these signal pathways as the targets will cast new lights for liver cancer treatment.
Key words: liver neoplasms     hepatocellular carcinoma     signaling pathway     therapeutic target     endothelial growth factor receptor     hepatitis B virus    

肝细胞癌(hepatocellular carcinoma,HCC) 是世界第五大常见肿瘤,占原发性肝脏肿瘤的90%[1],是我国最常见的一种原发性肝癌,更是全球恶性死亡中最重要的一个因素。目前尚不清楚肝癌的确切病因,本课题组前期研究发现,肝癌的发生很大程度上与乙型肝炎病毒(hepatitis B virus,HBV)感染有关[2, 3, 4]。肝癌的发生是个多步骤的过程,这一 过程遵循达尔文进化理论,即变异-选择-适应,包括慢性炎症、增生及恶性转化的形成。研究表明,多种细胞信号转导通路的异常活化参与了这一恶性转化过程的发展[5, 6]。目前发现的参与肝癌发生、发展、转移的信号通路主要包括以下几条:血管内皮细胞生长因子受体 (vascular endothelial growth factor receptor,VEGFR)、表皮生长因子受体(epidermal growth factor receptor,EGFR)、血小板衍生生长因子受体(platelet-derived growth factor receptor,PDGFR)、类胰岛素生长因子受体(insulin-like growth factors receptor,IGFR)等,这些信号通路的异常活化最终导致细胞增殖、血管形成、侵袭和转移及对凋亡耐受的发生[7]。目前肝癌的治疗方法有多种,包括药物对症治疗、手术治疗、放射治疗、生物免疫治疗等,但是这些治疗对肝癌的治愈效果不佳,预后不良。随着相关信号转导机制研究的进展,靶向疗法逐渐引起专家学者的重视。靶向调节肝癌增殖、侵袭、转移信号通路的药物为治疗这一疾病提供了可能。本文总结HCC主要相关信号转导通路及对应靶向治疗药物作用机制研究进展,详见表 1。

表 1 各信号通路与靶向治疗药物的对应关系 Tab 1 Correspondences between signaling pathways and targeted therapy
1 表皮生长因子信号通路

EGFR属于ERB受体酪氨酸激酶(receptor tyrosine kinases,RTKs)家族,又称ErbB-1,有胞外配体结合区、跨膜区及胞内区,其中胞内区具有酪氨酸激酶活性。EGFR与配体结合后形成同二聚体或异二聚体,磷酸化并激活下游多种信号如PI3K/Akt/mTOR/Ras/Mek/Erk等。EGFR的配体除EGF外,还包括转化生长因子α(transforming growth factor α,TGFα)、双向调节素(AREG)以及与肝素结合的EGF(HB-EGF)等[13]。研究表明EGFR在肝癌形成过程中过表达,这种过表达同细胞增殖分化及疾病分期相关。EGFR的表达往往能够预示肝癌患者的预后[14],因此,研究者提出EGFR可能是抑制肝癌的分子治疗靶点。

目前以EGFR为靶点的药物主要包括西妥昔单抗(cetuximab)和小分子的酪氨酸激酶抑制剂吉非替尼、厄罗替尼及拉帕替尼。临床试验表明,cetuximab对晚期HCC的反应率仅为0%~9%,中位无进展生存期为1.3~3.2个月,中位总生存期为6.2~13个月[10],表明目前以EGFR为靶点药物的有效性不容乐观,临床上通常与卡培他滨及奥沙利铂合用。

2 Ras/Raf/Mek/Erk通路

Ras/Raf/Mek/Erk通路又被称作MAPK通路,MAPK通路高度保守,对细胞增殖、分化至关重要,在HCC中通常是上调的[15]。该通路的异常激活与HCC的发生及恶性转化有着紧密的联系[16]。尽管在HCC中Ras、Raf很少发生突变,但与周围非瘤性组织及正常肝组织相比,Ras通路明显激活,有研究表明同非肿瘤组织相比,100%HCC标本检测到Ras的活化[16]。早期研究揭示HBV感染可以利用Raf/Mek/Erk通路控制肝细胞存活和病毒复制[17, 18],HBV基因组编码的HBx蛋白表达,促使Ras/Raf/Mek/Erk激酶活化,从而参与HCC的发生、发展。这些研究均表明该通路可能成为HBV感染后HCC患者的一种治疗方向。

目前正在进行临床研究的Ras抑制剂有索拉菲尼(sorafenib)、onafamib、regorafenib、AZD624,其中sorafenib可抑制多种激酶,除Raf激酶外,还有VEGFR-2/-3、PDGFR-β、Flt-3、c-Kit等,且已获FDA批准治疗晚期HCC,因此sorafenib最具有前景。临床研究表明,sorafenib组可将中位总生存期从7.9个月提升至10.7个月,疾病进展时间中位数从2.8个月延长到 5.5个月[19],将sorafenib与阿霉素联用能够使晚期HCC患者无进展期延长,总生存率提高。但sorafenib存在腹泻、出疹等不良反应,目前其主要用于HCC患者局部肝切除后预防复发的辅助治疗。近年研究还揭示,Mek抑制剂能够抑制肿瘤的发生及肝癌细胞增殖,选择性Mek抑制剂AZD6244可阻碍Erkl/2的激活,从而减慢肿瘤生长并诱导肿瘤细胞凋亡,且联用细胞抑制剂多柔比星可提高抗肿瘤活性[9]

3 PI3K/PTEN/Akt/mTOR通路

当生长因子与细胞表面特异性受体如EGFR、IGF-1R结合后磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)通路被激活,导致细胞异常增殖,与肝癌的发生、发展有密切的关系。HBV正是利用PI3K通路控制肝细胞的存活和病毒的复制。PI3K是一种异聚体蛋白,可使一系列膜磷脂磷酸化形成第二信使如PIP2、PIP3。第二信使可促进蛋白丝氨酸/苏氨酸激酶Akt的激活,使细胞基质中凋亡蛋白酶-9、促凋亡分子BAD、GSK-3β等磷酸化,从而靶向调节与细胞增殖、血管生成有关的转录因子。对部分肝切除术后肝癌组织的基因序列分析表明,发生PI3KCA突变的患者中约50%预后较差,其术后生存时间小于3年[20]。Akt的活化也是肝癌术后复发和预后较差的危险因素。Akt的激活还可调节哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)功能,最终导致细胞生存能力的增加。PTEN可使PIP3去磷酸化,抑制Akt的激活,从而负向调节该通路[21]。动物模型表明,肝细胞PTEN缺陷的大鼠均自发出现肝腺瘤,其中66%最终形成HCC,取这些大鼠的肝脏组织发现肝细胞高度增生,Akt异常活化[22]。研究发现,PTEN高表达时,HCC患者总生存率显著提高[21]。因此,PTEN激活剂与Akt抑制剂很可能成为HCC靶向治疗的新药物。

MK-2206是一种新型口服变构Akt抑制剂,可使普通抗血管生成治疗无效或不耐受的HCC晚期患者得到缓解。当sorafenib与MK-2206联合用药,可克服HCC细胞对sorafenib的抗性并达到有效浓度[10]。PI3K抑制剂如perifosine、Lv29004、wortmannin等都具有抗肿瘤活性,但仍未进行临床试验。近期体外研究表明mTOR抑制剂rapamycin及其类似物everolimus能够显著性地抑制HCC细胞的生长,并改善HCC患者的存活,有望成为HCC治疗的前景药物[23]

4 VEGFR通路

VEGF是刺激血管生成的最主要因子,在包括HCC的绝大多数肿瘤中表达上调。这种血管刺激因子可由多种肝细胞分泌,包括HCC细胞、肝星形细胞以及肿瘤浸润炎性细胞。有研究表明,VEGF表达状况与总生存期呈负相关,并且可以预测肝癌的预后[24]。因此,找到抑制肿瘤血管形成的药物可能成为HCC治疗的新靶点。

贝伐单抗是一种重组人VEGF单克隆抗体,已经用于治疗临床晚期HCC患者,临床观察表明贝伐单抗具有较好的耐受性,但仍存在出血、蛋白尿、血栓栓塞等副作用,其疗效仍需进一步的临床研究进行评估[11]。最近研究新发现的brivanib是一种多重RTK抑制剂,可同时选择性抑制VEGF及成纤维细胞生长因子 (fibroblast growth factor,FGF)信号,能够显著提高不可切除、晚期及转移性HCC患者的中位总生存期[25]。Brivanib耐受性较好,主要副作用包括腹泻、乏力、血压升高。目前正在研发的还有linifanib及andetanib,均具有较好的治疗HCC前景。

5 IGFR信号通路

IGFR信号通路由配体IGF-Ⅰ/Ⅱ以及膜受体相互作用。当HCC发生时,该信号通路被异常激活,IGF信号通路的激活能通过多种信号级联反应如P13K/Akt、MAPK通路抗HCC细胞凋亡,促进肿瘤生长。通路中IGF-Ⅱ、IGF-1R及IRS的过表达促进肿瘤细胞增殖并抑制凋亡,增加HCC的侵袭性。此外,在HBV相关的HCC患者,HBx蛋白促进IGF-Ⅱ表达,这解释了HBV促进癌症发生发展的学说[26]

目前研究的IGF-1R抑制剂主要是单克隆抗体IMC-A12,其能够降低HCC细胞的生存力及增殖力,动物实验证实IMC-A12可延迟肿瘤生长,诱导HCC细胞凋亡[12]。单克隆抗体AVE1642能够特异性阻滞IGF-1R信号,无明显副作用,且大部分进展期HCC患者接受治疗后能保持持久的疾病稳定状态。

6 其他信号通路

其他对HCC发生、发展起重要作用的信号通路还包括STAT3、TNF-α、NF-κB以及Wnt/β-连环蛋白信号通路等[27, 28, 29]。这些信号通路都可能成为HCC甚至其他一些恶性肿瘤的治疗靶点。

HCC的治疗选择较多,但是目前尚无疗效好、耐受强、副作用少的药物,寻找有效的治疗靶点成为攻克HCC的最大难题。对参与HCC发生、发展过程的各种信号通路进行深入研究发现,这些通路可能成为治疗HCC的前景药物靶点,应该予以重视。

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