精准医学时代下肝内胆管癌的发病机制与临床转化

尤文化; 梁渊; 吕凌

doi:10.3969/j.issn.1001-5256.2021.04.045

精准医学时代下肝内胆管癌的发病机制与临床转化

DOI: 10.3969/j.issn.1001-5256.2021.04.045

尤文化^{1, 2},
梁渊^{1, 2},
吕凌^2, ,

1.
南京医科大学生物医学工程与信息学院，南京 211166
2.
南京医科大学第一附属医院肝胆中心，南京 210029

基金项目:

国家自然科学基金 (81522020)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：尤文化负责文献检索，阅读及综述撰写；梁渊负责文献检索及分析汇总；吕凌负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
尤文化(1996—)，男，主要从事肝胆肿瘤的生物信息学与转化医学研究

通信作者:
吕凌，lvling@njmu.edu.cn

中图分类号: R735.8
计量
- 文章访问数: 920
- HTML全文浏览量: 276
- PDF下载量: 99
- 被引次数: 0
出版历程
- 收稿日期: 2020-09-16
- 录用日期: 2020-10-16
- 出版日期: 2021-04-20

Pathogenesis and clinical translation of intrahepatic cholangiocarcinoma in the era of precision medicine

Wenhua YOU^{1, 2},
Yuan LIANG^{1, 2},
Ling LYU^{2
, ,}

1.
School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
2.
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

摘要

摘要:
肝内胆管癌(ICC)是仅次于肝细胞癌的第二大肝脏恶性肿瘤，占所有原发性肝癌的15%~20%。近年来，全球ICC的发病率呈上升趋势。但因其起病隐匿，恶性程度高，侵袭能力强，多数患者就诊时就已处于终末期，失去了手术的最佳时机。随着二代测序技术的不断发展，使得ICC治疗不断向个体化、精准化方向发展。介绍了ICC在发病机制、分子分型、早期诊断方面等基础研究的进展，并回顾了近几年ICC的临床转化研究。希望通过其进展，为ICC的治疗和临床研究提供新思路。
- 胆管上皮癌 /
- 肿瘤微环境 /
- 诊断 /
- 治疗学
Abstract:
Intrahepatic cholangiocarcinoma (ICC) is an important liver malignancy next only to hepatocellular carcinoma, accounting for 15%-20% of primary liver cancer. In recent years, the incidence rate of ICC tends to increase globally; however, due to its insidious onset, high degree of malignancy, and strong invasive ability, most patients are in the advanced stage when attending the hospital and thus miss the most appropriate timing for surgery. With the continuous development of next-generation sequencing, the treatment of ICC gradually develops towards the direction of individualization and precision. This article introduces the basic research advances in the pathogenesis, molecular typing, and early diagnosis of ICC and reviews the clinical translational research of ICC in recent years, so as to provide new ideas for the treatment and clinical research of ICC.
- Cholangiocarcinoma /
- Tumor Microenvironment /
- Diagnosis /
- Therapeutics

HTML全文

表 1 ICC液体活检标志物

标志物	检测样本	特异度	敏感度	结论
CNV^[29]	胆汁	98.9%	75.0%	高准确度
CRP等^[30]	血清外泌体	-	-	显著高于癌前病变
CTC^[31]	外周血	-	-	与预后相关
注：-，原文未提及；CNV，拷贝数变异；CTC，循环肿瘤细胞。

下载: 导出CSV

参考文献(41)

[1]	KHAN SA, THOMAS HC, DAVIDSON BR, et al. Cholangiocarcinoma[J]. Lancet, 2005, 366(9493): 1303-1314. DOI: 10.1016/S0140-6736(05)67530-7
[2]	BRIDGEWATER J, GALLE PR, KHAN SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma[J]. J Hepatol, 2014, 60(6): 1268-1289. DOI: 10.1016/j.jhep.2014.01.021
[3]	SAHA SK, ZHU AX, FUCHS CS, et al. Forty-year trends in cholangiocarcinoma incidence in the U.S. : Intrahepatic disease on the rise[J]. Oncologist, 2016, 21(5): 594-599. DOI: 10.1634/theoncologist.2015-0446
[4]	LIU ZH, CHEN Z, MA LL, et al. Factors influencing the prognosis of patients with intrahepatic cholangiocarcinoma[J]. Acta Gastroenterol Belg, 2012, 75(2): 215-218. http://www.ncbi.nlm.nih.gov/pubmed/21431970
[5]	YOH T, HATANO E, SEO S, et al. Long-term survival of recurrent intrahepatic cholangiocarcinoma: The impact and selection of repeat surgery[J]. World J Surg, 2018, 42(6): 1848-1856. DOI: 10.1007/s00268-017-4387-7
[6]	HWANG S, LEE YJ, SONG GW, et al. Prognostic impact of tumor growth type on 7th AJCC staging system for intrahepatic cholangiocarcinoma: A single-center experience of 659 cases[J]. J Gastrointest Surg, 2015, 19(7): 1291-1304. DOI: 10.1007/s11605-015-2803-6
[7]	MOEINI A, SIA D, BARDEESY N, et al. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma[J]. Clin Cancer Res, 2016, 22(2): 291-300. DOI: 10.1158/1078-0432.CCR-14-3296
[8]	FAN B, MALATO Y, CALVISI DF, et al. Cholangiocarcinomas can originate from hepatocytes in mice[J]. J Clin Invest, 2012, 122(8): 2911-2915. DOI: 10.1172/JCI63212
[9]	SEKIYA S, SUZUKI A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes[J]. J Clin Invest, 2012, 122(11): 3914-3918. DOI: 10.1172/JCI63065
[10]	GUEST RV, BOULTER L, KENDALL TJ, et al. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma[J]. Cancer Res, 2014, 74(4): 1005-1010. DOI: 10.1158/0008-5472.CAN-13-1911
[11]	NAKAMURA H, ARAI Y, TOTOKI Y, et al. Genomic spectra of biliary tract cancer[J]. Nat Genet, 2015, 47(9): 1003-1010. DOI: 10.1038/ng.3375
[12]	FARSHIDFAR F, ZHENG S, GINGRAS MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles[J]. Cell Rep, 2017, 18(11): 2780-2794. DOI: 10.1016/j.celrep.2017.02.033
[13]	WANG L, ZHU H, ZHAO Y, et al. Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience[J]. J Transl Med, 2020, 18(1): 273. DOI: 10.1186/s12967-020-02437-2
[14]	ANDERSEN JB, THORGEIRSSON SS. Genetic profiling of intrahepatic cholangiocarcinoma[J]. Curr Opin Gastroenterol, 2012, 28(3): 266-272. DOI: 10.1097/MOG.0b013e3283523c7e
[15]	MENG F, WEHBE H, HENSON R, et al. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes[J]. Oncogene, 2008, 27(3): 378-386. DOI: 10.1038/sj.onc.1210648
[16]	PLIESKATT J, RINALDI G, FENG Y, et al. A microRNA profile associated with Opisthorchis viverrini-induced cholangiocarcinoma in tissue and plasma[J]. BMC Cancer, 2015, 15: 309. DOI: 10.1186/s12885-015-1270-5
[17]	MENG F, HENSON R, LANG M. et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines[J]. Gastroenterology, 2006, 130(7): 2113-2129. DOI: 10.1053/j.gastro.2006.02.057
[18]	ZHANG M, YANG H, WAN L, et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma[J]. J Hepatol, 2020, 73(5): 1118-1130. DOI: 10.1016/j.jhep.2020.05.039
[19]	MCNAMARA MG, TEMPLETON AJ, MAGANTI M, et al. Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer[J]. Eur J Cancer, 2014, 50(9): 1581-1589. DOI: 10.1016/j.ejca.2014.02.015
[20]	ZHOU SL, DAI Z, ZHOU ZJ, et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils[J]. Carcinogenesis, 2014, 35(3): 597-605. DOI: 10.1093/carcin/bgt397
[21]	SUBIMERB C, PINLAOR S, KHUNTIKEO N, et al. Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma[J]. Mol Med Rep, 2010, 3(4): 597-605. http://www.ncbi.nlm.nih.gov/pubmed/21472285
[22]	BOULTER L, GUEST RV, KENDALL TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited[J]. J Clin Invest, 2015, 125(3): 1269-1285. DOI: 10.1172/JCI76452
[23]	VIVIER E, UGOLINI S, BLAISE D, et al. Targeting natural killer cells and natural killer T cells in cancer[J]. Nat Rev Immunol, 2012, 12(4): 239-252. DOI: 10.1038/nri3174
[24]	SEEHAWER M, HEINZMANN F, D'ARTISTA L, et al. Necroptosis microenvironment directs lineage commitment in liver cancer[J]. Nature, 2018, 562(7725): 69-75. DOI: 10.1038/s41586-018-0519-y
[25]	JOB S, RAPOUD D, DOS SANTOS A, et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma[J]. Hepatology, 2020, 72(3): 965-981. DOI: 10.1002/hep.31092
[26]	CHAISAINGMONGKOL J, BUDHU A, DANG H, et al. Common molecular subtypes among asian hepatocellular carcinoma and cholangiocarcinoma[J]. Cancer Cell, 2017, 32(1): 57-70.e3. DOI: 10.1016/j.ccell.2017.05.009
[27]	SIA D, HOSHIDA Y, VILLANUEVA A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes[J]. Gastroenterology, 2013, 144(4): 829-840. DOI: 10.1053/j.gastro.2013.01.001
[28]	XU RH, WEI W, KRAWCZYK M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma[J]. Nat Mater, 2017, 16(11): 1155-1161. DOI: 10.1038/nmat4997
[29]	SHEN N, ZHANG D, YIN L, et al. Bile cell-free DNA as a novel and powerful liquid biopsy for detecting somatic variants in biliary tract cancer[J]. Oncol Rep, 2019, 42(2): 549-560. http://www.researchgate.net/publication/333518985_Bile_cell-free_DNA_as_a_novel_and_powerful_liquid_biopsy_for_detecting_somatic_variants_in_biliary_tract_cancer
[30]	ARBELAIZ A, AZKARGORTA M, KRAWCZYK M, et al. Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma[J]. Hepatology, 2017, 66(4): 1125-1143. DOI: 10.1002/hep.29291
[31]	YANG JD, CAMPION MB, LIU MC, et al. Circulating tumor cells are associated with poor overall survival in patients with cholangiocarcinoma[J]. Hepatology, 2016, 63(1): 148-158. DOI: 10.1002/hep.27944
[32]	LAMARCA A, PALMER DH, WASAN HS, et al. ABC-06 \| A randomised phase Ⅲ, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced/metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy[J]. J Clin Oncol, 2019, 37(15 Suppl): 4003.
[33]	BEKAⅡ-SAAB TS, VALLE JW, CUTSEM EV, et al. FIGHT-302: First-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements[J]. Future Oncol, 2020, 16(30): 2385-2399. DOI: 10.2217/fon-2020-0429
[34]	ABOU-ALFA GK, SAHAI V, HOLLEBECQUE A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study[J]. Lancet Oncol, 2020, 21(5): 671-684. DOI: 10.1016/S1470-2045(20)30109-1
[35]	ABOU-ALFA GK, MACARULLA T, JAVLE MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21(6): 796-807. DOI: 10.1016/S1470-2045(20)30157-1
[36]	BANG YJ, UENO M, MALKA D, et al. Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies[J]. J Clin Oncol, 2019, 37(15_Suppl): 4079. DOI: 10.1200/JCO.2019.37.15_suppl.4079
[37]	LIN J, SHI W, ZHAO S, et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing[J]. J Clin Oncol, 2018, 36(4 Suppl): 500. http://www.researchgate.net/publication/330096463_Lenvatinib_plus_checkpoint_inhibitors_in_patients_pts_with_advanced_intrahepatic_cholangiocarcinoma_ICC_Preliminary_data_and_correlation_with_next-generation_sequencing
[38]	CHEN WX, LI GX, HU ZN, et al. Significant response to anti-PD-1 based immunotherapy plus lenvatinib for recurrent intrahepatic cholangiocarcinoma with bone metastasis: A case report and literature review[J]. Medicine (Baltimore), 2019, 98(45): e17832. DOI: 10.1097/MD.0000000000017832
[39]	QIN S, CHEN Z, LIU Y, et al. A phase Ⅱ study of anti-PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer[J]. J Clin Oncol, 2019, 37(15 Suppl): 4074. http://www.researchgate.net/publication/333406920_A_phase_II_study_of_anti-PD-1_antibody_camrelizumab_plus_FOLFOX4_or_GEMOX_systemic_chemotherapy_as_first-line_therapy_for_advanced_hepatocellular_carcinoma_or_biliary_tract_cancer
[40]	OH D, LEE K, LEE D, et al. Phase Ⅱ study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ±tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC)[J]. J Clin Oncol, 2020, 38(15 Suppl): 4520. http://www.researchgate.net/publication/341632436_Phase_II_study_assessing_tolerability_efficacy_and_biomarkers_for_durvalumab_D_tremelimumab_T_and_gemcitabinecisplatin_GemCis_in_chemo-naive_advanced_biliary_tract_cancer_aBTC
[41]	SAHAI V, GRIFFITH K A, BEG M S, et al. A multicenter randomized phase Ⅱ study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01)[J]. J Clin Oncol, 2020, 38(15 Suppl): 4582.