Skip to main content

Advertisement

SpringerLink
Log in

The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All data and materials are available in this study.

References

  1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6. https://doi.org/10.1056/nejm197111182852108.

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  3. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57. https://doi.org/10.1038/35025220.

    Article  CAS  PubMed  Google Scholar 

  4. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10. https://doi.org/10.1038/nrc1093.

    Article  CAS  PubMed  Google Scholar 

  5. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9(6):685–93. https://doi.org/10.1038/nm0603-685.

    Article  CAS  PubMed  Google Scholar 

  6. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. https://doi.org/10.1038/nature10144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 1972;175(3):409–16. https://doi.org/10.1097/00000658-197203000-00014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8(6):425–37. https://doi.org/10.1038/nrc2397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410. https://doi.org/10.1038/nrc3064.

    Article  CAS  PubMed  Google Scholar 

  10. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62. https://doi.org/10.1126/science.1104819.

    Article  CAS  PubMed  Google Scholar 

  11. Shen G, Li Y, Du T, Shi G, Dai L, Chen X, et al. SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy. Neoplasma. 2012;59(5):486–93. https://doi.org/10.4149/neo_2012_062.

    Article  CAS  PubMed  Google Scholar 

  12. Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: progress, opportunities, and challenges. Annu Rev Physiol. 2019;81:505–34. https://doi.org/10.1146/annurev-physiol-020518-114700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shigeta K, Datta M, Hato T, Kitahara S, Chen IX, Matsui A, et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology. 2020;71(4):1247–61. https://doi.org/10.1002/hep.30889.

    Article  CAS  PubMed  Google Scholar 

  14. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905. https://doi.org/10.1056/NEJMoa1915745.

    Article  CAS  PubMed  Google Scholar 

  15. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  16. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53. https://doi.org/10.1053/j.gastro.2015.12.041.

    Article  PubMed  Google Scholar 

  17. Lau WY, Leung TW, Lai BS, Liew CT, Ho SK, Yu SC, et al. Preoperative systemic chemoimmunotherapy and sequential resection for unresectable hepatocellular carcinoma. Ann Surg. 2001;233(2):236–41. https://doi.org/10.1097/00000658-200102000-00013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. EASL Clinical Practice Guidelines. Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. https://doi.org/10.1016/j.jhep.2018.03.019.

    Article  Google Scholar 

  19. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. https://doi.org/10.1056/NEJMoa0708857.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. https://doi.org/10.1016/s1470-2045(08)70285-7.

    Article  CAS  PubMed  Google Scholar 

  21. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73. https://doi.org/10.1016/s0140-6736(18)30207-1.

    Article  CAS  PubMed  Google Scholar 

  22. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. https://doi.org/10.1016/s0140-6736(16)32453-9.

    Article  CAS  PubMed  Google Scholar 

  23. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–96. https://doi.org/10.1016/s1470-2045(18)30937-9.

    Article  CAS  PubMed  Google Scholar 

  24. Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014:638747. https://doi.org/10.1155/2014/638747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Okamoto K, Ikemori-Kawada M, Jestel A, von König K, Funahashi Y, Matsushima T, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2015;6(1):89–94. https://doi.org/10.1021/ml500394m.

    Article  CAS  PubMed  Google Scholar 

  26. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841–4. https://doi.org/10.1038/362841a0.

    Article  CAS  PubMed  Google Scholar 

  27. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 1993;143(2):401–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sun C, Li J, Wang B, Shangguan J, Figini M, Shang N, et al. Tumor angiogenesis and bone metastasis—correlation in invasive breast carcinoma. J Immunol Methods. 2018;452:46–52. https://doi.org/10.1016/j.jim.2017.10.006.

    Article  CAS  PubMed  Google Scholar 

  29. Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 1978;38(9):2651–60.

    CAS  PubMed  Google Scholar 

  30. Lu LC, Hsu CH, Hsu C, Cheng AL. Tumor heterogeneity in hepatocellular carcinoma: facing the challenges. Liver Cancer. 2016;5(2):128–38. https://doi.org/10.1159/000367754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakagawa T, Gonda K, Kamei T, Cong L, Hamada Y, Kitamura N, et al. X-ray computed tomography imaging of a tumor with high sensitivity using gold nanoparticles conjugated to a cancer-specific antibody via polyethylene glycol chains on their surface. Sci Technol Adv Mater. 2016;17(1):387–97. https://doi.org/10.1080/14686996.2016.1194167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fadnes HO, Reed RK, Aukland K. Interstitial fluid pressure in rats measured with a modified wick technique. Microvasc Res. 1977;14(1):27–36. https://doi.org/10.1016/0026-2862(77)90138-8.

    Article  CAS  PubMed  Google Scholar 

  33. Niwano M, Arii S, Mori A, Ishigami S, Harada T, Mise M, et al. Inhibition of tumor growth and microvascular angiogenesis by the potent angiogenesis inhibitor, TNP-470, in rats. Surg Today. 1998;28(9):915–22. https://doi.org/10.1007/s005950050252.

    Article  CAS  PubMed  Google Scholar 

  34. Mazzetti S, Frigerio S, Gelati M, Salmaggi A, Vitellaro-Zuccarello L. Lycopersicon esculentum lectin: an effective and versatile endothelial marker of normal and tumoral blood vessels in the central nervous system. Eur J Histochem. 2004;48(4):423–8. https://doi.org/10.4081/916.

    Article  CAS  PubMed  Google Scholar 

  35. Sørensen BS, Horsman MR. Tumor hypoxia: impact on radiation therapy and molecular pathways. Front Oncol. 2020;10:562. https://doi.org/10.3389/fonc.2020.00562.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chen JC, Chuang HY, Hsu FT, Chen YC, Chien YC, Hwang JJ. Sorafenib pretreatment enhances radiotherapy through targeting MEK/ERK/NF-κB pathway in human hepatocellular carcinoma-bearing mouse model. Oncotarget. 2016;7(51):85450–63. https://doi.org/10.18632/oncotarget.13398.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med. 2016;13(4):496–504. https://doi.org/10.20892/j.issn.2095-3941.2016.0066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou K, Zhang JW, Wang QZ, Liu WY, Liu JL, Yao L, et al. Apatinib, a selective VEGFR2 inhibitor, improves the delivery of chemotherapeutic agents to tumors by normalizing tumor vessels in LoVo colon cancer xenograft mice. Acta Pharmacol Sin. 2019;40(4):556–62. https://doi.org/10.1038/s41401-018-0058-y.

    Article  CAS  PubMed  Google Scholar 

  39. Matsumoto S, Batra S, Saito K, Yasui H, Choudhuri R, Gadisetti C, et al. Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res. 2011;71(20):6350–9. https://doi.org/10.1158/0008-5472.Can-11-2025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nilsson MB, Zage PE, Zeng L, Xu L, Cascone T, Wu HK, et al. Multiple receptor tyrosine kinases regulate HIF-1alpha and HIF-2alpha in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors. Oncogene. 2010;29(20):2938–49. https://doi.org/10.1038/onc.2010.60.

    Article  CAS  PubMed  Google Scholar 

  41. Yu W, Zhao S, Zhao Y, Fatema CN, Murakami M, Nishijima KI, et al. Changes in tumor oxygen state after sorafenib therapy evaluated by (18)F-fluoromisonidazole hypoxia imaging of renal cell carcinoma xenografts. Oncol Lett. 2017;14(2):2341–6. https://doi.org/10.3892/ol.2017.6371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kimura T, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109(12):3993–4002. https://doi.org/10.1111/cas.13806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Deng H, Kan A, Lyu N, Mu L, Han Y, Liu L, et al. Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. Liver Cancer. 2020;9(3):338–57. https://doi.org/10.1159/000505695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Y. Ishigaki for technical assistance. This work was supported by grants from the Japan Society for the Promotion of Science (JSPS).

Funding

A portion of this work was supported by a Grant-in-Aid for Challenging Exploratory Research (19K22549) from the Japan Society for the Promotion of Science (JSPS) (K.G.), a Grant-in-Aid for Scientific Research (C) (19K12749) from the JSPS (N.K. and K.G.), and a Grant-in-Aid for Scientific Research (C) (18K08697) from the JSPS (R.N. and K.G.).

Author information

Authors and Affiliations

  1. Department of Medical Physics, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Norikazu Une, Mayumi Takano-Kasuya, Narufumi Kitamura, Tomoya Inose, Chihiro Kato & Kohsuke Gonda

  2. Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

    Norikazu Une, Mineto Ohta, Ryuichi Nishimura, Shigehito Miyagi, Michiaki Unno & Takashi Kamei

  3. Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

    Hiroshi Tada & Takanori Ishida

  4. International Center for Synchrotron Radiation Innovation Smart (SRIS), Tohoku University, 2-1-1, Katahira, Aoba-ku, Sendai, 980-8577, Japan

    Kohsuke Gonda

Authors
  1. Norikazu Une
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mayumi Takano-Kasuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Narufumi Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mineto Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomoya Inose
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chihiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryuichi Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroshi Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shigehito Miyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takanori Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michiaki Unno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takashi Kamei
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kohsuke Gonda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NU and KG conceived and designed the experiments. NU, TI, and CK performed the experiments. NU, TI, and CK analyzed the data. NU, MO, TI, CK, RN, HT, SM, TI, MU, TK, and KG discussed the results. NU and KG wrote the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Kohsuke Gonda.

Ethics declarations

Conflict of interest

All authors declare no commercial or financial conflict of interest.

Ethical approval

This paper does not involve human tissues or human data. All animal procedures were reviewed and approved by the Committee on Animal Experiments at Tohoku University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 7468 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Une, N., Takano-Kasuya, M., Kitamura, N. et al. The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors. Med Oncol 38, 60 (2021). https://doi.org/10.1007/s12032-021-01503-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-021-01503-z

Keywords

Search

Navigation