-
摘要:
肝细胞癌（hepatocellular carcinoma, HCC）是世界上发病率和死亡率最高的恶性肿瘤之一。研究发现，CXCL12-CXCR4/CXCR7生物轴可通过自分泌和（或）旁分泌机制调控HCC细胞的生长、血管生成、免疫逃逸及侵袭转移等关键步骤，有可能成为HCC防治新靶点和预后评价新标志。本文就当前国内外研究CXCL12-CXCR4/CXCR7生物轴在肝癌发生和发展过程中的作用以及与此相关的信号转导途径进行综述。
Abstract:Hepatocellular carcinoma(HCC) is one of the malignant tumors with the highest morbidity and mortality rates in the world. Studies have shown that CXCL12-CXCR4/CXCR7 biological axis can modulate the growth of HCC cells, angiogenesis, immune escape, invasion and metastasis via autocrine and/or paracrine mechanisms, and may become a new therapeutic target and valuable prognostic marker for HCC. This review aims to summarize the multiple functions of CXCL12-CXCR4/CXCR7 axis in HCC development and progression, as well as the signal transductions that are essential to this process.
-
Key words:
- Hepatocellular carcinoma /
- CXCL12 /
- CXCR4 /
- CXCR7
-
0 引言
宫颈小细胞神经内分泌癌（small cell neuroendocrine carcinoma, SCNEC）是一种较为罕见的原发于宫颈的神经内分泌性肿瘤，约占宫颈恶性肿瘤的1%~2%[1-2]。在各种类型的宫颈癌中，SCNEC是一种侵袭性强的病理类型[3-8]。但因为该类病例较少，目前尚无规范化的治疗。本研究对101例宫颈小细胞神经内分泌癌患者的临床病理资料及生存状况进行分析，旨在探讨SCNEC合理的治疗方案及预后相关因素，为此类患者治疗及预后判断提供临床依据。
1 资料与方法
1.1 临床资料
收集2007年1月—2018年6月在江西省妇幼保健院确诊并完成治疗的101例宫颈小细胞神经内分泌癌患者作为研究对象。患者确诊年龄25~73岁，中位年龄44岁，其中41~50岁者有40例。宫颈局部肿瘤直径 > 4 cm患者34例，≤4 cm患者67例。患者临床资料及年龄分布见表 1。所有患者均知情同意。
表 1 101例SCNEC患者临床病理特征Table 1 Clinical and pathological features of 101 SCNEC patients
1.2 方法
1.2.1 研究对象纳入标准
（1）所有患者接受治疗前均经江西省妇幼保健院病理确诊为宫颈小细胞神经内分泌癌；（2）临床分期盆腔检查均经三位以上有经验的妇科肿瘤专业医师检查确定；（3）治疗前均未接受任何干预性治疗，且初始治疗及后续治疗均在同一机构完成；（4）纳入研究的患者治疗模式均为手术+术后补充放化疗（下文简称手术治疗组）或根治性放化疗，且按计划完成全部治疗；（5）全部患者术后病理检查均在同一医院完成；（6）建立了完整的病历档案，并持续随访，具备完整的住院及门诊复查病历资料。
1.2.2 手术方式
72例手术治疗患者手术方式为广泛子宫切除+盆腔淋巴结切除术±腹主动脉旁淋巴结切除术，其中47例行腹主动脉旁淋巴结切除术。69例行双附件切除，其余3例保留一侧卵巢且进行了保留卵巢的组织活检。
1.2.3 放疗
放疗包括体外照射+腔内后装治疗，体外照射采用全盆腔体外照射+中央遮盖体外照射。体外照射剂量：全盆照射肿瘤剂量30~40 Gy，中央遮盖照射剂量15~25 Gy，放疗频率及强度：每周5次，每次分割剂量2 Gy。腔内后装采用高剂量率后装治疗设备，放射源为铱192。放疗剂量参照点A点累积剂量要求60~70 Gy；B点累积剂量要求54~56 Gy。放疗期间均给予铂类为基础的同步化疗。
1.2.4 随访
通过电话或门诊复查方式进行随访，截止时间为2018年9月。
1.3 统计学方法
采用GraphPad7.0统计软件对不同组间患者生存率进行显著性比较。生存分析采用Kaplan-Meier法，生存率的比较采用Log rank检验。P < 0.05为差异有统计学意义。
2 结果
72例手术组患者中，2例失访，19例死亡，51例生存。19例死亡患者生存时间1~63月，中位生存时间19月，平均生存时间18.5月。51例生存的患者中，生存时间1~139月，中位生存时间39月，平均生存时间47.3月。随访5年以上共33例，生存20例，五年生存率60.6%。
29例根治性放化疗患者中，随访5年以上20例，其中2例失访，死亡15例，生存3例，五年生存率15%。生存时间1~75月，中位生存时间21月。3例生存患者年龄分别为40岁、41岁、46岁，临床分期均为ⅡB期，病理均为单纯的宫颈小细胞神经内分泌癌，化疗方案均为多西他赛+卡铂，放疗给予根治性同步放化疗。ⅠB1期~ⅡA期手术治疗组患者生存率优于ⅡB期~Ⅳ期期根治性放化疗组患者（P=0.0025），见图 1。
72例接受手术治疗的患者均行宫颈癌根治术+盆腔淋巴结切除术，47例行腹主动脉旁淋巴结切除术，其中1例（1/47, 2.12%）腹主动脉旁淋巴结阳性。27例（27/72, 37.5%）盆腔淋巴结阳性。淋巴结阳性与阴性患者生存曲线比较差异有统计学意义，淋巴结阴性患者生存优于淋巴结阳性患者（P=0.0004），见图 2。
![]()
图 2 盆腔淋巴结阳性和阴性手术患者生存曲线Figure 2 Survival curves of surgical SCNEC patients with pelvic lymph node positive and negative72例手术治疗的患者中，按病理类型分，单纯SCNEC例41例，混合其他病理类型者31例，其中混合有腺癌19例，鳞癌9例，腺鳞癌3例。混合型与单纯型SCNEC生存曲线比较差异无统计学意义（P=0.0546），见图 3。
3 讨论
WHO分类将宫颈神经内分泌肿瘤分为低级别神经内分泌肿瘤（包括类癌及非典型类癌）和高级别神经内分泌肿瘤（包括小细胞神经内分泌癌和大细胞神经内分泌癌）。目前无公认的、规范有效的治疗方案，对于宫颈神经内分泌肿瘤多参照常见宫颈癌的分期治疗原则，主张手术、化疗和放疗的综合性治疗，但其治疗是否应有别于宫颈鳞癌需要更大样本、多中心的研究。美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）指南也将SCNEC列入特殊类型宫颈癌。
关于SCNEC患者生存率及预后方面的研究，Ishikawa等的一项多中心研究显示淋巴血管间隙受侵是患者的总生存率及无进展生存率的重要预后因素，盆腔淋巴结转移是DFS的重要预后影响因素[9]。Cohen等研究发现Ⅰ~ⅡA、ⅡB~ⅣA、ⅣB期5年生存率分别为36.8%、9.8%和0[10]，本研究结果显示临床分期与预后密切相关，各期别5年生存率均较以往文献报道略高。FIGO分期是较为公认的影响患者预后的最重要的独立危险因素[11-12]。由于SCNEC侵袭性强，易发生远处转移，有学者认为早期SCNEC患者手术联合化疗的预后优于单纯手术者[13-14]。本研究中ⅠB~ⅡA期患者均采用手术+放化疗综合治疗，5年总生存率60%以上，提示手术联合术后放化疗对此类患者疗效较好。
宫颈小细胞神经内分泌癌早期容易发生转移，但从72例早期患者手术情况发现，仅1例（1.39%）发生卵巢转移。提示对于存在生育要求的年轻SCNEC患者，是否一定要行卵巢切除有待进一步研究证实。研究证实，SCNEC好发转移器官为肺、脑、肝，预后差[15-16]。
此外，几乎所有文献均支持此类肿瘤早期即容易发生远处转移，本研究资料中，死亡病例主要病因为肺转移、全身转移，临床观察也支持上述观点。关于淋巴结转移，有研究认为，即使是早期的SCNEC患者，淋巴结转移也非常普遍，淋巴结转移率为41.6%~57%[17]。本研究中，72例早期SCNEC患者手术后病理提示淋巴结转移22例，转移率37.5%，与文献报道接近，但是对于腹主动脉旁淋巴结，72例患者中47例患者行腹主动脉旁淋巴结活检或切除，仅1例发生腹主动脉旁淋巴结转移，转移率仅为2.13%，远低于盆腔淋巴结转移率。这一研究结果提示我们，即便是早期SCNEC患者，化疗对于控制转移也有重要的临床意义。
与以往报道相比，本研究中手术患者术后均补充了放化疗，且均达到6个疗程，其中49例采用紫杉醇+铂类化疗方案，23例采用顺铂+环磷酰胺+表阿霉素化疗方案，提示手术后放化疗的必要性。
总之，宫颈小细胞神经内分泌癌发病率低、恶性程度高、易发生远处转移和复发，患者预后差、死亡率高、有独特的病理特征，诊断主要依据病理诊断和免疫组织化学结果可提高其诊断的准确率。由于研究样本少，尚需大量的临床资料及多中心研究探索最佳早期诊断及治疗的方法。
-
[1] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108. doi: 10.3322/caac.21262
[2] Liepelt A, Tacke F. Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases[J]. Am J Physiol Gastrointest Liver Physiol, 2016, 311(2): G203-9. doi: 10.1152/ajpgi.00193.2016
[3] Ray P, Lewin SA, Mihalko LA, et al. Secreted CXCL12 (SDF-1) forms dimers under physiological conditions[J]. Biochem J, 2012, 442(2): 433-42. doi: 10.1042/BJ20111341
[4] Abraham M, Klein S, Bulvik B, et al. The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by down-regulating ERK BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression[J]. Leukemia, 2017 [Epub ahead of print].
[5] Wang X, Cao Y, Zhang S, et al. Stem cell autocrine CXCL12/CXCR4 stimulates invasion and metastasis of esophageal cancer[J]. Oncotarget, 2017, 8(22): 36149-60.
[6] Hu F, Miao L, Zhao Y, et al. A Meta-analysis for C-X-C chemokine receptor type 4 as a prognostic marker and potential drug target in hepatocellular carcinoma[J]. Drug Des Devel Ther, 2015, 9: 3625-33. http://www.ncbi.nlm.nih.gov/pubmed/26203228
[7] Taromi S, Kayser G, Catusse J, et al. CXCR4 antagonists suppress small cell lung cancer progression[J]. Oncotarget, 2016, 7(51): 85185-95. https://www.ncbi.nlm.nih.gov/pubmed/27835905
[8] Shi A, Shi H, Dong L, et al. CXCR7 as a chemokine receptor for SDF-1 promotes gastric cancer progression via MAPK pathways[J]. Scand J Gastroenterol, 2017, 52(6-7): 745-53. doi: 10.1080/00365521.2017.1300681
[9] San-Miguel T, Pinto S, Navarro L, et al. Expression of the Chemokine Receptors CXCR3, CXCR4, CXCR7 and Their Ligands in Rhabdomyosarcoma[J]. Pathol Oncol Res, 2015, 21(4): 1191-9. doi: 10.1007/s12253-015-9947-2
[10] Szpakowska M, Dupuis N, Baragli A, et al. Human herpesvirus 8-encoded chemokine vCCL2/vMIP-Ⅱ is an agonist of the atypical chemokine receptor ACKR3/CXCR7[J]. Biochem Pharmacol, 2016, 114: 14-21. doi: 10.1016/j.bcp.2016.05.012
[11] Sánchez-Alcañiz JA, Haege S, Mueller W, et al. Cxcr7 controls neuronal migration by regulating chemokine responsiveness[J]. Neuron, 2011, 69(1): 77-90. doi: 10.1016/j.neuron.2010.12.006
[12] Qiu F, Li Y, Fu Q, et al. Stromal Cell-Derived Factor 1 Increases Tetrodotoxin-Resistant Sodium Currents Nav1.8 and Nav1.9 in Rat Dorsal Root Ganglion Neurons via Different Mechanisms[J].Neurochem Res, 2016, 41(7): 1587-603. doi: 10.1007/s11064-016-1873-5
[13] Dillenburg-Pilla P, Patel V, Mikelis CM, et al. SDF-1/CXCL12 induces directional cell migration and spontaneous metastasis via a CXCR4/Gαi/mTORC1 axis[J]. FASEB J, 2015, 29(3): 1056-68. doi: 10.1096/fj.14-260083
[14] Lv B, Yang X, Lv S, et al. Retraction Note to:CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma[J]. Mol Neurobiol, 2017, 54(3): 2380. doi: 10.1007/s12035-017-0464-z
[15] Waldmann TA. JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics[J]. Mol Cell Endocrinol, 2017, 451: 66-70. doi: 10.1016/j.mce.2017.02.019
[16] Kallifatidis G, Munoz D, Singh RK, et al. β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation[J]. Mol Cancer Res, 2016, 14(5): 493-503. doi: 10.1158/1541-7786.MCR-15-0498
[17] Coggins NL, Trakimas D, Chang SL, et al. CXCR7 Controls Competition for Recruitment of β-Arrestin 2 in Cells Expressing Both CXCR4 and CXCR7[J]. PLoS One, 2014, 9(6): e98328. doi: 10.1371/journal.pone.0098328
[18] Lin L, Han MM, Wang F, et al. CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression[J]. Cell Death Dis, 2014, 5: e1488. doi: 10.1038/cddis.2014.392
[19] Shah AD, Bouchard MJ, Shieh AC. Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling[J]. PLoS One, 2015, 10(11): e0142337. doi: 10.1371/journal.pone.0142337
[20] Liu H, Liu Y, Liu W, et al. EZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma[J]. Nat Commun, 2015, 6: 8494. doi: 10.1038/ncomms9494
[21] Xue TC, Jia QA, Bu Y, et al. CXCR7 correlates with the differentiation of hepatocellular carcinoma and suppresses HNF4α expression through the ERK pathway[J]. Oncol Rep, 2014, 32(6): 2387-96. doi: 10.3892/or.2014.3501
[22] 罗娅, 金海, 文国容, 等.肝细胞肝癌诱导分化治疗研究进展[J].世界华人消化杂志, 2015, 29: 4665-72. http://www.cnki.com.cn/Article/CJFDTOTAL-XXHB201529011.htm Luo Y, Jin H, Wen GR, et al. Advances in differentiation therapy of hepatocellular carcinoma[J]. Shi Jie Hua Ren Xiao Hua Za Zhi, 2015, 29: 4665-72. http://www.cnki.com.cn/Article/CJFDTOTAL-XXHB201529011.htm
[23] Wang Y, Yu H, Shan Y, et al. EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1/CXCR4 signaling pathway[J]. J Exp Clin Cancer Res, 2016, 35: 65. doi: 10.1186/s13046-016-0339-6
[24] Xu J, Liang J, Meng YM, et al. Vascular CXCR4 expression promotes vessel sprouting and sensitivity to sorafenib treatment inhepato cellular carcinoma[J]. Clin Cancer Res, 2017 [Epub ahead of print].
[25] Chen Y, Teng F, Wang G, et al. Overexpression of CXCR7 induces angiogenic capacity of human hepatocellular carcinoma cells via the AKT signaling pathway[J]. Oncol Rep, 2016, 36(4): 2275-81. doi: 10.3892/or.2016.5045
[26] Li W, Gomez E, Zhang Z. Immunohistochemical expression of stromal cell-derived factor-1 (SDF-1) and CXCR4 ligand receptor system in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2007, 26(4): 527-33. http://www.ncbi.nlm.nih.gov/pubmed/18365549
[27] Shen X, Li N, Li H, et al. Increased prevalence of regulatory T cells in the tumor microenvironment and its correlation with TNM stage of hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2010, 136(11): 1745-54. doi: 10.1007/s00432-010-0833-8
[28] Chen Y, Ramjiawan R, Reiberger T, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice[J]. Hepatology, 2015, 61(5): 1591-602. doi: 10.1002/hep.27665
[29] Yang L, Huang J, Ren X, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis[J]. Cancer Cell, 2008, 13(1): 23-35. doi: 10.1016/j.ccr.2007.12.004
[30] 戴小珍, 熊新, 王兰, 等. CXCR7-shRNA慢病毒载体对人肝癌细胞生长及侵袭能力的抑制作用[J].南方医科大学学报, 2013, 33(7): 994-8. http://www.cnki.com.cn/Article/CJFDTOTAL-DYJD201307012.htm Dai XZ, Xiong X, Wang L, et al. Effects of CXCR7-shRNA lentiviral vector on the growth and invasiveness of human hepatoma carcinoma cells in vitro[J]. Nan Fang Yi Ke Da Xue Xue Bao, 2013, 33(7): 994-8. http://www.cnki.com.cn/Article/CJFDTOTAL-DYJD201307012.htm
[31] Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells[J]. Oncogene, 2005, 24(27): 4462-71. doi: 10.1038/sj.onc.1208621
[32] Tan W, Zhu S, Cao J, et al. Inhibition of MMP-2 Expression Enhances the Anti-tumor Effect of Sorafenib in Hepatocellular Carcinoma by Suppressing PI3K/AKT/mTOR Pathway[J]. Oncol Res, 2017 [Epub ahead of print].
[33] García-Irigoyen O, Latasa MU, Carotti S, et al. Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis[J]. Hepatology, 2015, 62(1): 166-78. doi: 10.1002/hep.27798
[34] Zhang R, Pan X, Huang Z, et al. Osteopontin enhances the expression and activity of MMP-2 via the SDF-1/CXCR4 axis in hepatocellular carcinoma cell lines[J]. PLoS One, 2011, 6(8): e23831. doi: 10.1371/journal.pone.0023831
[35] Reichl P, Haider C, Grubinger M, et al. TGF-β in epithelial to mesenchymal transition and metastasis of liver carcinoma[J]. Curr Pharm Des, 2012, 18(27): 4135-47. doi: 10.2174/138161212802430477
[36] Bertran E, Crosas-Molist E, Sancho P, et al. Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells[J]. Hepatology, 2013, 58(6): 2032-44. doi: 10.1002/hep.26597
[37] Cepeda EB, Dediulia T, Fernando J, et al. Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells[J]. Biochim Biophys Acta, 2015, 1853(5): 1205-18. doi: 10.1016/j.bbamcr.2015.02.012
[38] Wu YC, Tang SJ, Sun GH, et al. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer[J]. Oncogene, 2016, 35(16): 2123-32. doi: 10.1038/onc.2015.274
[39] Yu H, Zhang L, Liu P. CXCR7 signaling induced epithelial-mesenchymal transition by AKT and ERK pathways in epithelial ovarian carcinomas[J]. Tumour Biol, 2015, 36(3): 1679-83. doi: 10.1007/s13277-014-2768-1
[40] Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis[J]. Nature, 2001, 410(6824): 50-6. doi: 10.1038/35065016
[41] 施国英, 施德金, 吕伟标, 等.基质细胞衍化生长因子-1及其受体CXCR4在肝细胞癌和肝硬化中的表达[J].中华肝脏病杂志, 2007, 15(4): 276-8. http://d.wanfangdata.com.cn/Periodical/zhgzbzz200704009 Shi GY, Shi DJ, LYU WB, et al. A study of CXCR4/SDF-1 in hepatocellular carcinoma and liver cirrhosis[J]. Zhonghua Gan Zang Bing Za Zhi, 2007, 15(4): 276-8. http://d.wanfangdata.com.cn/Periodical/zhgzbzz200704009
[42] Liu H, Pan Z, Li A, et al. Roles of Chemokine Receptor 4 (CXCR4) and Chemokine Ligand 12 (CXCL12) in Metastasis of Hepatocellular Carcinoma Cells[J]. Cell Mol Immunol, 2008, 5(5): 373-8. doi: 10.1038/cmi.2008.46
下载:
计量
- 文章访问数: 1728
- HTML全文浏览量: 360
- PDF下载量: 1001
