Clinical and Translational Oncology

, Volume 20, Issue 5, pp 639–646 | Cite as

Application of EGFR inhibitor reduces circulating tumor cells during transcatheter arterial embolization

  • L. Zhu
  • R. LiuEmail author
  • W. Zhang
  • S. Qian
  • J. Wang
Research Article



Transcatheter arterial embolization (TAE) has been widely used in treating non-curative hepatocellular carcinoma (HCC). However, it is noticed that TAE may cause invasion of some cancer cells into circulation, resulting in distal metastasis and poor therapeutic outcome. Here, we aimed to reduce the side effects of TAE using the inhibitors for epidermal growth factor receptor (EGFR).


Transient hepatic artery ligation (HAL) was used as a mouse model for TAE. EGFR inhibitors were applied. Tumor size, presence of tumor cells in circulation, distal tumor formation, and activation of genes associated with tumor cell invasion and metastasis were analyzed.


Inhibitors for EGFR significantly reduced the size of primary tumor, presence of tumor cells in circulation, and distal tumor formation after HAL. Further studies showed that EGFR inhibition suppressed several genes associated with tumor cell invasion and metastasis, such as vascular endothelial growth factor-A, stromal cell-derived factor 1, and Slug.


EGFR inhibitor application may reduce circulating cancer cells during TAE and thus improve the therapy for advanced HCC.


Transcatheter arterial embolization (TAE) Transient hepatic artery ligation (HAL) Hepatocellular carcinoma (HCC) Epidermal growth factor receptor (EGFR) Vascular endothelial growth factor-A (VEGF-A) Stromal cell-derived factor 1 (SDF-1) Slug 


Compliance with ethical standards

Conflict of interest

The authors have declared that no competing interests exist.

Informed consent

The study was approved by the Local Ethics Committee of Zhongshan Hospital of Fudan University, China.


  1. 1.
    Verslype C, Van Cutsem E, Dicato M, Arber N, Berlin JD, Cunningham D, et al. The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008. Ann Oncol. 2009;20(Suppl 7):vii1–6. doi: 10.1093/annonc/mdp281.PubMedGoogle Scholar
  2. 2.
    Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48(Suppl 1):S20–37. doi: 10.1016/j.jhep.2008.01.022.CrossRefPubMedGoogle Scholar
  3. 3.
    Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48(4):1312–27. doi: 10.1002/hep.22506.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Arizumi T, Ueshima K, Minami T, Kono M, Chishina H, Takita M, et al. Effectiveness of sorafenib in patients with transcatheter arterial chemoembolization (TACE) refractory and intermediate-stage hepatocellular carcinoma. Liver cancer. 2015;4(4):253–62. doi: 10.1159/000367743.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fu S, Chen S, Liang C, Liu Z, Zhu Y, Li Y, et al. Texture analysis of intermediate-advanced hepatocellular carcinoma: prognosis and patients’ selection of transcatheter arterial chemoembolization and sorafenib. Oncotarget. 2017;8(23):37855–65. doi: 10.18632/oncotarget.13675.CrossRefPubMedGoogle Scholar
  6. 6.
    Nishikawa H, Osaki Y, Iguchi E, Takeda H, Nakajima J, Matsuda F, et al. Comparison of the efficacy of transcatheter arterial chemoembolization and sorafenib for advanced hepatocellular carcinoma. Exp Ther Med. 2012;4(3):381–6. doi: 10.3892/etm.2012.611.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fang ZT, Wang GZ, Zhang W, Qu XD, Liu R, Qian S, et al. Transcatheter arterial embolization promotes liver tumor metastasis by increasing the population of circulating tumor cells. OncoTargets Ther. 2013;6:1563–72. doi: 10.2147/OTT.S52973.Google Scholar
  8. 8.
    Murakami M, Nagano H, Kobayashi S, Wada H, Nakamura M, Marubashi S, et al. Effects of pre-operative transcatheter arterial chemoembolization for resectable hepatocellular carcinoma: implication of circulating cancer cells by detection of alpha-fetoprotein mRNA. Exp Ther Med. 2010;1(3):485–91. doi: 10.3892/etm_00000076.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sainz B Jr, Heeschen C. Standing out from the crowd: cancer stem cells in hepatocellular carcinoma. Cancer Cell. 2013;23(4):431–3. doi: 10.1016/j.ccr.2013.03.023.CrossRefPubMedGoogle Scholar
  10. 10.
    Chiba T, Kamiya A, Yokosuka O, Iwama A. Cancer stem cells in hepatocellular carcinoma: recent progress and perspective. Cancer Lett. 2009;286(2):145–53. doi: 10.1016/j.canlet.2009.04.027.CrossRefPubMedGoogle Scholar
  11. 11.
    Chiba T, Kanai F, Iwama A, Yokosuka O. Circulating cancer stem cells: a novel prognostic predictor of hepatocellular carcinoma. Hepatobiliary surgery and nutrition. 2013;2(1):4–6. doi: 10.3978/j.issn.2304-3881.2012.09.02.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Nagano H, Ishii H, Marubashi S, Haraguchi N, Eguchi H, Doki Y, et al. Novel therapeutic target for cancer stem cells in hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2012;19(6):600–5. doi: 10.1007/s00534-012-0543-5.CrossRefPubMedGoogle Scholar
  13. 13.
    Nel I, David P, Gerken GG, Schlaak JF, Hoffmann AC. Role of circulating tumor cells and cancer stem cells in hepatocellular carcinoma. Hepatol Int. 2014;8(3):321–9. doi: 10.1007/s12072-014-9539-3.CrossRefPubMedGoogle Scholar
  14. 14.
    Fan ST, Yang ZF, Ho DW, Ng MN, Yu WC, Wong J. Prediction of posthepatectomy recurrence of hepatocellular carcinoma by circulating cancer stem cells: a prospective study. Ann Surg. 2011;254(4):569–76. doi: 10.1097/SLA.0b013e3182300a1d.CrossRefPubMedGoogle Scholar
  15. 15.
    Lai HC, Yeh CC, Jeng LB, Huang SF, Liao PY, Lei FJ, et al. Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells. Oncotarget. 2016;7(29):46448–65. doi: 10.18632/oncotarget.10186.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Luo J, Wang P, Wang R, Wang J, Liu M, Xiong S, et al. The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma. Oncotarget. 2016;7(8):9525–37. doi: 10.18632/oncotarget.6672.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhu L, Zhang W, Wang J, Liu R. Evidence of CD90+CXCR4+ cells as circulating tumor stem cells in hepatocellular carcinoma. Tumour Biol. 2015;36(7):5353–60. doi: 10.1007/s13277-015-3196-6.CrossRefPubMedGoogle Scholar
  18. 18.
    Kumar A, Bhanja A, Bhattacharyya J, Jaganathan BG. Multiple roles of CD90 in cancer. Tumour Biol. 2016;37(9):11611–22. doi: 10.1007/s13277-016-5112-0.CrossRefPubMedGoogle Scholar
  19. 19.
    Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene. 2016;35(7):816–26. doi: 10.1038/onc.2015.139.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhao H, Guo L, Zhao H, Zhao J, Weng H, Zhao B. CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget. 2015;6(7):5022–40. doi: 10.18632/oncotarget.3217.CrossRefPubMedGoogle Scholar
  21. 21.
    Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43. doi: 10.1016/S0140-6736(05)67700-8.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang B, Wang D, Ji TF, Shi L, Yu JL. Overexpression of lncRNA ANRIL up-regulates VEGF expression and promotes angiogenesis of diabetes mellitus combined with cerebral infarction by activating NF-kappaB signaling pathway in a rat model. Oncotarget. 2017;8(10):17347–59. doi: 10.18632/oncotarget.14468.PubMedGoogle Scholar
  23. 23.
    Yang M, Tian M, Zhang X, Xu J, Yang B, Yu J, et al. Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. Oncotarget. 2017;. doi: 10.18632/oncotarget.18555.Google Scholar
  24. 24.
    Zhu L, Wang G, Fischbach S, Xiao X. Suppression of microRNA-205-5p in human mesenchymal stem cells improves their therapeutic potential in treating diabetic foot disease. Oncotarget. 2017;. doi: 10.18632/oncotarget.17012.Google Scholar
  25. 25.
    Li XL, Liu L, Li DD, He YP, Guo LH, Sun LP, et al. Integrin beta4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma. Scientific reports. 2017;7:40464. doi: 10.1038/srep40464.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chen WX, Zhang ZG, Ding ZY, Liang HF, Song J, Tan XL, et al. MicroRNA-630 suppresses tumor metastasis through the TGF-beta- miR-630-Slug signaling pathway and correlates inversely with poor prognosis in hepatocellular carcinoma. Oncotarget. 2016;7(16):22674–86. doi: 10.18632/oncotarget.8047.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Sun D, Sun B, Liu T, Zhao X, Che N, Gu Q, et al. Slug promoted vasculogenic mimicry in hepatocellular carcinoma. J Cell Mol Med. 2013;17(8):1038–47. doi: 10.1111/jcmm.12087.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lin WH, Yeh SH, Yeh KH, Chen KW, Cheng YW, Su TH, et al. Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice. Proc Natl Acad Sci USA. 2016;113(42):11937–42. doi: 10.1073/pnas.1613466113.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zou CD, Zhao WM, Wang XN, Li Q, Huang H, Cheng WP, et al. MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. Oncotarget. 2016;7(1):266–78. doi: 10.18632/oncotarget.5689.CrossRefPubMedGoogle Scholar
  30. 30.
    Yang J, Pei H, Luo H, Fu A, Yang H, Hu J, et al. Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways. Oncotarget. 2017;8(1):915–32. doi: 10.18632/oncotarget.13687.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang L, Sun H, Wang X, Hou N, Zhao L, Tong D, et al. EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway. Oncotarget. 2016;7(29):45302–16. doi: 10.18632/oncotarget.9605.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Chang L, Wang G, Jia T, Zhang L, Li Y, Han Y, et al. Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma. Oncotarget. 2016;7(17):23988–4004. doi: 10.18632/oncotarget.8115.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Lanaya H, Natarajan A, Komposch K, Li L, Amberg N, Chen L, et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 2014;16(10):972–81. doi: 10.1038/ncb3031 (1–7).CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mrad M, Imbert C, Garcia V, Rambow F, Therville N, Carpentier S, et al. Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting M1 macrophage response in melanoma. Oncotarget. 2016;7(44):71873–86. doi: 10.18632/oncotarget.12380.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zhang W, Wang Z, Luo Y, Zhong D, Luo Y, Zhou D. GATA3 expression correlates with poor prognosis and tumor-associated macrophage infiltration in peripheral T cell lymphoma. Oncotarget. 2016;7(40):65284–94. doi: 10.18632/oncotarget.11673.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Jimenez-Garcia L, Herranz S, Higueras MA, Luque A, Hortelano S. Tumor suppressor ARF regulates tissue microenvironment and tumor growth through modulation of macrophage polarization. Oncotarget. 2016;7(41):66835–50. doi: 10.18632/oncotarget.11652.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Low HB, Png CW, Li C, Wang Y, Wong SB, Zhang Y. Monocyte-derived factors including PLA2G7 induced by macrophage-nasopharyngeal carcinoma cell interaction promote tumor cell invasiveness. Oncotarget. 2016;7(34):55473–90. doi: 10.18632/oncotarget.10980.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Zhang H, Zhang W, Sun X, Dang R, Zhou R, Bai H, et al. Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization. Oncotarget. 2016;7(31):50099–116. doi: 10.18632/oncotarget.10318.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35. doi: 10.1038/nri978nri978.CrossRefPubMedGoogle Scholar
  40. 40.
    Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci USA. 2014;111(13):E1211–20. doi: 10.1073/pnas.1321347111.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95. doi: 10.1172/JCI59643.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96. doi: 10.1038/ni.1937.CrossRefPubMedGoogle Scholar
  43. 43.
    Ono M. Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci. 2008;99(8):1501–6. doi: 10.1111/j.1349-7006.2008.00853.x.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2017

Authors and Affiliations

  1. 1.Department of Interventional RadiologyZhongshan Hospital of Fudan UniversityShanghaiChina

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