基于射频消融治疗肝癌在兔VX2模型上的研究论文_李小月,孙红花(通讯作者)

基于射频消融治疗肝癌在兔VX2模型上的研究论文_李小月,孙红花(通讯作者)

延边大学附属医院 肿瘤科 133000

摘要:肝细胞癌(HCC)以其高发病率,高死亡率及不断上升的发病率成为位居世界范围第五位的最常见的恶性肿瘤。值得注意的是手术切除及肝移植是肝癌主要治疗方法,然而大多数患者由于合并肝硬化,失去了手术和肝移植的机会。目前,包括射频消融(RFA)、经皮无水乙醇注射法(PEI)、微波固化消融术(MCT)、肝肿瘤动脉栓塞术(TACE)以及其他各种局部疗法,已成为肝癌治疗中可供选择的对象。在诸多的技术中,RFA因安全、有效等特点成为当前使用最广泛的治疗方法。迄今,因不彻底的治疗致使残癌的出现降低了RFA在肝癌中的疗效。为了提高RFA在肝癌中的疗效,使用兔VX2肝癌模型进行了一些体内实验,实验以单纯RFA,RFA与药物或是其他局部疗法联合。兔VX2肝癌模型的肿瘤具有快速生长、与人类肝细胞癌相似的特点,是一个理想的肝癌模型,被广泛应用于影像学及其他各类实验研究。为了说明RFA在肝癌治疗中的意义,本文回顾了应用兔VX2肝癌模型研究RFA所得的最新发现。

关键词:肝细胞癌;RFA;射频消融;VX2肿瘤;残余瘤

肝癌在世界范围内的医疗卫生系统中占有重要的地位,因其高发病率,高死亡率及逐年增长的发病率[1,2]。尽管大多数患者在发现肝癌时已无法行手术或肝移植,但这依然是使肝癌获得治愈的主要手段。手术中的难点与肿瘤位置、大小、数目,有无侵犯血管及额外肝组织,以及患者的一般状态、肝脏功能等密切相关[3–5]。仅有约20%的肝癌病例被认为是可以手术切除的。迄今,RFA、PEI、MCT、TACE 及其他各种局部疗法因其安全、微创、高效的优点为肝癌的治疗提供了选择[6]。经证实,由于治疗不彻底而致肿瘤残余及治疗后局部复发降低了RFA在HCC治疗中的疗效,这可能与肿瘤周边血管[7]或肿瘤直径相关。一些研究表明,RFA治疗不充分残余瘤进展与不同因素及分子机制相关[8–12],特别是与各类肿瘤进展相关的炎性反应[13,14]。炎症反应在RFA作用位点处受热破坏的肝肿瘤诱发,可致HCC肿瘤的进展[14]。为了提高RFA在HCC中的疗效,同时避免残癌的出现,利用兔VX2肝癌模型设计进行一些体内实验:单纯RFA,RFA联合药物或其他局部疗法[12,15–18]。

兔VX2肿瘤模型广泛用于实验肿瘤学。VX2肿瘤被认为是未分化鳞状细胞癌,在兔骨骼肌中具有快速增长、血管丰富及易增殖的特点[19]。如前所述VX2细胞的移植可通过注入肿瘤细胞悬液或植入实体瘤块(新鲜或冰冻)实现[20]。因VX2肿瘤的快速生长性及与人类肝肿瘤的相似性使其成为理想的肝癌模型的代表。

1.一代VX2肝肿瘤模型基于局部治疗研究的概述

一些研究表明肝内植入实体瘤块的成功率高于注入瘤细胞悬液[21–23],而超声引导下植入肝肿瘤获得了不错的成功率[24]。值得注意的是对于VX2肿瘤而言首选的植入位点是肝脏的左外侧叶,这有利于为日后供血动脉造影导管插入时提供合适的角度。经一些研究人员证实肿瘤植入2-4周后会发展成为2-3cm大小的瘤结节[25]。

据报道超声可用于追踪实体瘤的生长并能检测出肿瘤坏死[26]。未坏死的肿瘤能够很好评估肿瘤在局部治疗实验中的反应。包括RFA和TACE在内的局部疗法在肝细胞癌的临床治疗中起到重要的作用[27]。有关应用兔VX2肝癌模型进行的临床前期研究得到的许多证据都表明了局部疗法的安全性和高效性,特别是结合辅助成分效果尤为突出。Gholamrezanezhad等人在兔VX2肿瘤模型动脉内注射70-150um的阿霉素洗脱珠(DEBs),并评估了其药代动力学(PK)和栓塞疗效[28]。有报道表明在VX2肝转移瘤模型中承载伊立替康的微球和DEBs微球可引起瘤结节显著性坏死[29]。Xia等人表明动脉内白介素-12基因转染联合化疗栓塞在VX2兔肝细胞癌中表现出强效的抗肿瘤作用[30]。应用兔VX2肝癌模型所做的另一项研究证实电穿孔法介导肝动脉栓塞化疗(E-TACE)提高了肝肿瘤对经导管定向灌注的化疗药物的摄取[31]。此外,Deng等人发现在载有VX2肝肿瘤的兔模型上TACE联合经肝动脉给药恩度(一种血管生成抑制剂),可有效抑制与TACE相关的血管形成的生物指标[32]。一项与此类似的研究表明氯喹与TACE联合可增强在肝癌中的抗肿瘤作用。作者表明氯喹作为一种传统的治疗疟疾药物[33],可提升TACE在兔VX2肝肿瘤模型中的抗肿瘤作用。其他研究证实在兔VX2肝癌模型中阿霉素单药局部化疗与TACE相比,抗肿瘤作用有限[34]。最近,有报道称TACE与强化型纳米颗粒、高强度聚焦超声及肿瘤外科手术精准整合后应用于VX2肝癌模型,能有效提高肝细胞癌的治疗效果,可作为一个新型高效的临床肿瘤治疗方案或形式[35]。在VX2肿瘤中诱导抗肿瘤T细胞免疫应答和细胞毒方面RFA与TRL9兴奋具有协同作用[17]。

2.射频消融治疗肝癌在兔VX2模型中的实验研究

RFA被认为是一种热效应,通过加热肿瘤组织至高温引起肿瘤细胞破坏[36]。经常被用于早期肝癌的治疗。RFA不彻底会降低其在HCC中的疗效,这点很重要。因肝脏的解剖结构、RFA的作用机制、HCC的病理特征及炎性反应等因素,残癌的出现在所难免。尽管RFA可将目标温度设定在105-115°C,但因肿瘤附近大血管的“热沉”效应,只有电极周围的组织可达到目标温度[37]。许多证据表明RFA后残余瘤进展迅速[38,39]。此外,这类肿瘤可转变为恶性间叶肿瘤,变得极具侵袭性,预后差[40,41]。应用兔VX2肝癌模型进行一些体内实验旨在提高RFA的疗效,并弄清残余瘤快速进展的机制。Ke等人在肝内植入VX2肿瘤结节的兔子中行RFA选用不同的射频温度(55,70,85°C),建立相应温度下的残余VX2肝癌模型。结果表明低温RFA能促进残余肝VX2瘤的进展。事实上,肝癌的进展和转移涉及不同的分子因子,如IL-6,PCNA,MMP-9,VEGF,HGF[42,43]。作者表明通过诱导一些像PCNA,MMP-9,VEGF,HGF、IL-6的分子因子过表达可促进残余VX2肿瘤的进展[12]。另有研究表明,RFA在靶点处可诱发炎症反应促进残癌的进展,而阿司匹林可用于抑制RFA后动物体内炎症反应的发生,同时降低与炎症反应相关的残余病灶的进展[15]。

结论

经由各项研究显示炎症反应和低温度RFA可能是导致肝VX2残余瘤快速进展的重要因素。低温度使RFA治疗肝癌不彻底,阿司匹林作为一种抗炎药物应用于RFA可抑制残癌的进展。联合治疗(药物或其他疗法)可有效提高RFA在肝癌中的疗效。各种局部疗法在肝癌的治疗中具有潜在的协同作用。未来研究需证实,具有治疗潜力的药物及其他局部治疗技术可在RFA治疗HCC过程中起辅助作用。

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参考文献:

[1]El-Serag HB.Hepatocellular carcinoma.N Engl J Med.2011;365(12):1118–27.

[2]Shariff MI,Cox IJ,Gomaa AI,Khan SA,Gedroyc W,Taylor-Robinson SD.Hepatocellular carcinoma:current trends in worldwide epidemiology,risk factors,diagnosis and therapeutics.Expert Rev Gastroenterol Hepatol.2009;3(4):353–67.

[3]Cho YK,Kim JK,Kim WT,Chung JW.Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma:a Markov model analysis.Hepatology.2010;51(4):1284–90.

[4]Lee WS,Yun SH,Chun HK,Lee WY,Kim SJ,Choi SH,et al.Clinical outcomes of hepatic resection and radiofrequency ablation in patients with solitary colorectal liver metastasis.J Clin Gastroenterol.2008;42(8):945–9.

[5]Mulier S,Ruers T,Jamart J,Michel L,Marchal G,Ni Y.Radiofrequency ablation versus resection for resectable colorectal liver metastases:time for a randomized trial? An update.Dig Surg.2008;25(6):445–60.

[6]Lau WY,Lai EC.The current role of radiofrequency ablation in the management of hepatocellular carcinoma:a systematic review.Ann Surg.2009;249(1):20–5.

[7] Chen X,Liu HP,Li M,Qiao L.Advances in non-surgical management of primary liver cancer.World J Gastroenterol.2014;20(44):16630–8.

[8] Kong J,Kong L,Kong J,Ke S,Gao J,Ding X,et al.After insufficient radiofrequency ablation,tumor-associated endothelial cells exhibit enhanced angiogenesis and promote invasiveness of residual hepatocellular carcinoma.J Transl Med.2012;10:230.

[9] Kong J,Kong J,Pan B,Ke S,Dong S,Li X,et al.Insufficient radiofrequency ablation promotes angiogenesis of residual hepatocellular carcinoma via HIF-1alpha/VEGFA.PLoS One.2012;7(5):e37266.

[10] Dong S,Kong J,Kong F,Kong J,Gao J,Ke S,et al.Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways.J Transl Med.2013;11:273.

[11] Zhang N,Wang L,Chai ZT,Zhu ZM,Zhu XD,Ma DN,et al.Incomplete radiofrequency ablation enhances invasiveness and metastasis of residual cancer of hepatocellular carcinoma cell HCCLM3 via activating beta-catenin signaling.PLoS One.2014;9(12):e115949.

[12] Ke S,Ding XM,Kong J,Gao J,Wang SH,Cheng Y,et al.Low temperature of radiofrequency ablation at the target sites can facilitate rapid progression of residual hepatic VX2 carcinoma.J Transl Med.2010;8:73.

[13] Wu Y,Zhou BP.Inflammation:a driving force speeds cancer metastasis.Cell Cycle.2009;8(20):3267–73.

[14] Schleimer RP.Inflammation:Basic principles and clinical correlates edited by John Gallin,Ira Goldstein and Ralph Snyderman,Raven Press,1987.$219.00(xvii + 995 pages)ISBN 0 88167 344 7.Immunol Today.1988;9(10):327.

[15]Jiang T,Zhang X,Ding J,Duan B,Lu S.Inflammation and cancer:inhibiting the progression of residual hepatic VX2 carcinoma by anti-inflammatory drug after incomplete radiofrequency ablation.Int J Clin Exp Pathol.2015;8(11):13945–56.

[16]Weinberg BD,Blanco E,Lempka SF,Anderson JM,Exner AA,Gao J.Combined radiofrequency ablation and doxorubicin-eluting polymer implants for liver cancer treatment.J Biomed Mater Res A.2007;81(1):205–13.

[17]Behm B,Di Fazio P,Michl P,Neureiter D,Kemmerling R,Hahn EG,et al.Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation.Gut.2016;65(1):134–43.

[18] Fan L,He Z,Ma K,Huang X,Zhou D,Feng X,et al.Hepatic VX2 tumor in rabbits:treated with radio frequency ablation and evaluated with enhanced CT.Zhonghua Gan Zang Bing Za Zhi.2002;10(5):362–5.

[19] Maruyama H,Matsutani S,Saisho H,Kamiyama N,Mine Y,Hirata T,et al.Sonographic shift of hypervascular liver tumor on blood pool harmonic images with definity:time-related changes of contrast-enhanced appearance in rabbit VX2 tumor under extra-low acoustic power.Eur J Radiol.2005;56(1):60–5.

[20] Parvinian A,Casadaban LC,Gaba RC.Development,growth,propagation,and angiographic utilization of the rabbit VX2 model of liver cancer:a pictorial primer and “how to” guide.Diagn Interv Radiol.2014;20(4):335–40.

[21]Virmani S,Harris KR,Szolc-Kowalska B,Paunesku T,Woloschak GE,Lee FT,et al.Comparison of two different methods for inoculating VX2 tumors in rabbit livers and hind limbs.J Vasc Interv Radiol.2008;19(6):931–6.

[22] Chen JH,Lin YC,Huang YS,Chen TJ,Lin WY,Han KW.Induction of VX2 carcinoma in rabbit liver:comparison of two inoculation methods.Lab Anim.2004;38(1):79–84.

[23]Sun JH,Zhang YL,Nie CH,Yu XB,Xie HY,Zhou L,et al.Considerations for two inoculation methods of rabbit hepatic tumors:Pathology and image features.Exp Ther Med.2012;3(3):386–90.

[24]Luo W,Zhou X,Zheng X,He G,Yu M,Li Q,et al.Role of sonography for implantation and sequential evaluation of a VX2 rabbit liver tumor model.J Ultrasound Med.2010;29(1):51–60.

[25]Wang D,Bangash AK,Rhee TK,Woloschak GE,Paunesku T,Salem R,et al.Liver tumors:monitoring embolization in rabbits with VX2 tumors–transcatheter intraarterial first-pass perfusion MR imaging.Radiology.2007;245(1):130–9.

[26]Luo W,Zhou X,Zheng X,He G,Yu M,Li Q,et al.Role of sonography for implantation and sequential evaluation of a VX2 rabbit liver tumor model.J Ultrasound Med.2010;29(1):51–60.

[27]Bimonte S,Barbieri A,Palaia R,Leongito M,Albino V,Piccirillo M,et al.An overview of loco-regional treatments in patients and mouse models for hepatocellular carcinoma.Infect Agent Cancer.2015;10:9.

[28]Gholamrezanezhad A,Mirpour S,Geschwind JH,Rao P,Loffroy R,Pellerin O,et al.Evaluation of 70-150-mum doxorubicin-eluting beads for transcatheter arterial chemoembolization in the rabbit liver VX2 tumour model.Eur Radiol.2016[Epub ahead of print].

[29] Namur J,Pascale F,Maeda N,Sterba M,Ghegediban SH,Verret V,et al.Safety and efficacy compared between irinotecan-loaded microspheres HepaSphere and DC bead in a model of VX2 liver metastases in the rabbit.J Vasc Interv Radiol.2015;26(7):1067–75.e3.

[30]Xia X,Li X,Feng G,Zheng C,Liang H,Zhou G.Intra-arterial interleukin-12 gene delivery combined with chemoembolization:anti-tumor effect in a rabbit hepatocellular carcinoma(HCC)model.Acta Radiol.2013;54(6):684–9.

[31] Guo Y,Zhang Y,Jin N,Klein R,Nicolai J,Lewandowski RJ,et al.Electroporation-mediated transcatheter arterial chemoembolization in the rabbit VX2 liver tumor model.Invest Radiol.2012;47(2):116–20.

[32]Deng G,Zhao DL,Li GC,Yu H,Teng GJ.Combination therapy of transcatheter arterial chemoembolization and arterial administration of antiangiogenesis on VX2 liver tumor.Cardiovasc Intervent Radiol.2011;34(4):824–32.

[33]Carew JS,Medina EC,Esquivel 2nd JA,Mahalingam D,Swords R,Kelly K,et al.Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation.J Cell Mol Med.2010;14(10):2448–59.

[34]Cho SK,Shin SW,Do YS,Jang KT,Choo SW,Park KB,et al.Single-bolus regional chemotherapy with doxorubicin versus chemoembolization in a rabbit VX2 tumor model.Diagn Interv Radiol.2011;17(4):374–80.

[35]You Y,Wang Z,Ran H,Zheng Y,Wang D,Xu J,et al.Nanoparticle-enhanced synergistic HIFU ablation and transarterial chemoembolization for efficient cancer therapy.Nanoscale.2016;8(7):4324–39.

[36] Curley SA.Radiofrequency ablation of malignant liver tumors.Oncologist.2001;6(1):14–23.

[37] Rossi S,Garbagnati F,Lencioni R,Allgaier HP,Marchiano A,Fornari F,et al.Percutaneous radio-frequency thermal ablation of nonresectable hepatocellular carcinoma after occlusion of tumor blood supply.Radiology.2000;217(1):119–26.

[38] Seki T,Tamai T,Ikeda K,Imamura M,Nishimura A,Yamashiki N,et al.Rapid progression of hepatocellular carcinoma after transcatheter arterial chemoembolization and percutaneous radiofrequency ablation in the primary tumour region.Eur J Gastroenterol Hepatol.2001;13(3):291–4.

[39]Ruzzenente A,Manzoni GD,Molfetta M,Pachera S,Genco B,Donataccio M,et al.Rapid progression of hepatocellular carcinoma after Radiofrequency Ablation.World J Gastroenterol.2004;10(8):1137–40.

[40] Kasugai H,Osaki Y,Oka H,Kudo M,Seki T,Osaka Liver Cancer Study G.Severe complications of radiofrequency ablation therapy for hepatocellular carcinoma:an analysis of 3,891 ablations in 2,614 patients.Oncology.2007;72 Suppl 1:72–5.

[41] Obara K,Matsumoto N,Okamoto M,Kobayashi M,Ikeda H,Takahashi H,et al.Insufficient radiofrequency ablation therapy may induce further malignant transformation of hepatocellular carcinoma.Hepatol Int.2008;2(1):116–23.

[42]Stroescu C,Dragnea A,Ivanov B,Pechianu C,Herlea V,Sgarbura O,et al.Expression of p53,Bcl-2,VEGF,Ki67 and PCNA and prognostic significance in hepatocellular carcinoma.J Gastrointestin Liver Dis.2008;17(4):411–7.

[43]Yang P,Yuan W,He J,Wang J,Yu L,Jin X,et al.Overexpression of EphA2,MMP-9,and MVD-CD34 in hepatocellular carcinoma:Implications for tumor progression and prognosis.Hepatol Res.2009;39(12):1169–77

论文作者:李小月,孙红花(通讯作者)

论文发表刊物:《健康世界》2016年第19期

论文发表时间:2016/10/26

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基于射频消融治疗肝癌在兔VX2模型上的研究论文_李小月,孙红花(通讯作者)
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