Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm. While ATL cells in peripheral blood (PB-ATL) are sensitive to anti-CC chemokine receptor 4 treatment, non–PB-ATLs, including lymph node ATLs (LN-ATLs), are more aggressive and resistant. We examined characteristic cytokines and growth factors that allow non–PB-ATLs to proliferate and invade compared with PB-ATLs. Protein array analysis revealed hepatocyte growth factor (HGF) and C-C motif chemokine 2 (CCL2) were significantly upregulated in non–PB-ATLs compared with PB-ATLs. The HGF membrane receptor, c-Met, was expressed in PB-ATL and non–PB-ATL cell lines, but CCR2, a CCL2 receptor, was not. Immunohistochemical analysis in clinical ATLs revealed high HGF expression in LNs, pharynx, bone marrow, and tonsils. The HGF/c-Met signaling pathway was active downstream in non–PB-ATLs. Downregulation of HGF/c-Met by siRNA or chemical inhibitors decreased in vitro and in vivo proliferation and invasion by non–PB-ATLs. Treatment with bromodomain and extra-terminal motif inhibitor suppressed HGF expression and decreased levels of histone H3 lysine 27 acetylation (H3K27Ac) and bromodomain-containing protein 4 (BRD4) binding promoter and enhancer regions, suppressing non–PB-ATL cellular growth. Our data indicate H3K27Ac/BRD4 epigenetics regulates the HGF/c-MET pathway in ATLs; targeting this pathway may improve treatment of aggressive non–PB-ATLs.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Expression of HGF in ATL cell lines and clinical samples.
Fig. 2: HGF promotes ATL cell proliferation and invasion.
Fig. 3: Effects of HGF/c-Met signaling and its downstream pathway on ATL cell growth.
Fig. 4: Regulation of HGF expression by epigenetic mechanisms.
Fig. 5: Serum HGF expression in clinical samples.

Similar content being viewed by others

References

  1. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977;50:481–92.

    Article  CAS  Google Scholar 

  2. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980;77:7415–9.

    Article  CAS  Google Scholar 

  3. Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita KI, et al. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA. 1981;78:6476–80.

    Article  CAS  Google Scholar 

  4. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br J Haematol. 1991;79:428–37.

    Article  CAS  Google Scholar 

  5. Katsuya H, Ishitsuka K, Utsunomiya A, Hanada S, Eto T, Moriuchi Y, et al. Treatment and survival among 1594 patients with ATL. Blood. 2015;126:2570–7.

    Article  CAS  Google Scholar 

  6. Yamada Y, Kamihira S, Murata K, Yamamura M, Maeda T, Tsukasaki K, et al. Frequent hepatic involvement in adult T cell leukemia: comparison with non-Hodgkin’s lymphoma. Leuk Lymphoma. 1997;26:327–35.

    Article  CAS  Google Scholar 

  7. Yoshie O, Fujisawa R, Nakayama T, Harasawa H, Tago H, Izawa D, et al. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood. 2002;99:1505–11.

    Article  CAS  Google Scholar 

  8. Hieshima K, Nagakubo D, Nakayama T, Shirakawa AK, Jin Z, Yoshie O. Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells. J Immunol. 2008;180:931–9.

    Article  CAS  Google Scholar 

  9. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30:837–42.

    Article  CAS  Google Scholar 

  10. Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015;169:672–82.

    Article  CAS  Google Scholar 

  11. Ishida T, Utsunomiya A, Jo T, Yamamoto K, Kato K, Yoshida S, et al. Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: updated follow-up analysis of phase I and II studies. Cancer Sci. 2017;108:2022–9.

    Article  CAS  Google Scholar 

  12. Umino A, Nakagawa M, Utsunomiya A, Tsukasaki K, Taira N, Katayama N, et al. Clonal evolution of adult T-cell leukemia/lymphoma takes place in the lymph nodes. Blood. 2011;117:5473–8.

    Article  CAS  Google Scholar 

  13. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47:1304–15.

    Article  CAS  Google Scholar 

  14. Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A, et al. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kappaB pathway in adult T cell leukemia and other cancers. Cancer Cell. 2012;21:121–35.

    Article  CAS  Google Scholar 

  15. Fujikawa D, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K, et al. Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood. 2016;127:1790–802.

    Article  CAS  Google Scholar 

  16. Yamagishi M, Hori M, Fujikawa D, Ohsugi T, Honma D, Adachi N, et al. Targeting excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas. Cell Rep. 2019;29:2321–37.e2327.

    Article  CAS  Google Scholar 

  17. Ding X, Ji J, Jiang J, Cai Q, Wang C, Shi M, et al. HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis. Cell Death Dis. 2018;9:867.

    Article  Google Scholar 

  18. Hartmann S, Bhola NE, Grandis JR. HGF/Met signaling in head and neck cancer: impact on the tumor microenvironment. Clin Cancer Res. 2016;22:4005–13.

    Article  CAS  Google Scholar 

  19. Kwon Y, Smith BD, Zhou Y, Kaufman MD, Godwin AK. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene. 2015;34:144–53.

    Article  CAS  Google Scholar 

  20. Choi YL, Tsukasaki K, O’Neill MC, Yamada Y, Onimaru Y, Matsumoto K, et al. A genomic analysis of adult T-cell leukemia. Oncogene. 2007;26:1245–55.

    Article  CAS  Google Scholar 

  21. Imaizumi Y, Murota H, Kanda S, Hishikawa Y, Koji T, Taguchi T, et al. Expression of the c-Met proto-oncogene and its possible involvement in liver invasion in adult T-cell leukemia. Clin Cancer Res. 2003;9:181–7.

    CAS  PubMed  Google Scholar 

  22. Onimaru Y, Tsukasaki K, Murata K, Imaizumi Y, Choi YL, Hasegawa H, et al. Autocrine and/or paracrine growth of aggressive ATLL cells caused by HGF and c-Met. Int J Oncol. 2008;33:697–703.

    CAS  PubMed  Google Scholar 

  23. Oki S, Ohta T, Shioi G, Hatanaka H, Ogasawara O, Okuda Y, et al. ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data. EMBO Rep. 2018;19:e46255.

    Article  Google Scholar 

  24. Oshiro A, Tagawa H, Ohshima K, Karube K, Uike N, Tashiro Y, et al. Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma. Blood. 2006;107:4500–7.

    Article  CAS  Google Scholar 

  25. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27:5410–7.

    Article  CAS  Google Scholar 

  26. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117:5827–34.

    Article  CAS  Google Scholar 

  27. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25:3109–15.

    Article  CAS  Google Scholar 

  28. Nakagawa M, Shaffer AL 3rd, Ceribelli M, Zhang M, Wright G, Huang DW, et al. Targeting the HTLV-I-regulated BATF3/IRF4 transcriptional network in adult T Cell Leukemia/Lymphoma. Cancer Cell. 2018;34:286–297.e210.

    Article  CAS  Google Scholar 

  29. Rutella S, Bonanno G, Procoli A, Mariotti A, de Ritis DG, Curti A, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood. 2006;108:218–27.

    Article  CAS  Google Scholar 

  30. Bonanno G, Mariotti A, Procoli A, Folgiero V, Natale D, De Rosa L, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J Transl Med. 2012;10:247.

    Article  CAS  Google Scholar 

  31. Masaki A, Ishida T, Maeda Y, Suzuki S, Ito A, Takino H, et al. Prognostic significance of tryptophan catabolism in adult T-cell Leukemia/Lymphoma. Clin Cancer Res. 2015;21:2830–9.

    Article  CAS  Google Scholar 

  32. Skibinski G, Skibinska A, James K. Hepatocyte growth factor (HGF) protects c-met-expressing Burkitt’s lymphoma cell lines from apoptotic death induced by DNA damaging agents. Eur J Cancer. 2001;37:1562–9.

    Article  CAS  Google Scholar 

  33. Miyoshi I, Kubonishi I, Sumida M, Hiraki S, Tsubota T, Kimura I, et al. A novel T-cell line derived from adult T-cell leukemia. Gan. 1980;71:155–6.

    CAS  PubMed  Google Scholar 

  34. Sugamura K, Fujii M, Kannagi M, Sakitani M, Takeuchi M, Hinuma Y. Cell surface phenotypes and expression of viral antigens of various human cell lines carrying human T-cell leukemia virus. Int J Cancer. 1984;34:221–8.

    Article  CAS  Google Scholar 

  35. Naoe T, Akao Y, Yamada K, Utsumi KR, Koike K, Shamoto M, et al. Cytogenetic characterization of a T-cell line, ATN-1, derived from adult T-cell leukemia cells. Cancer Genet Cytogenet. 1988;34:77–88.

    Article  CAS  Google Scholar 

  36. Suzuki S, Masaki A, Ishida T, Ito A, Mori F, Sato F, et al. Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma. Cancer Sci. 2012;103:1764–73.

    Article  CAS  Google Scholar 

  37. Xu C, Plattel W, van den Berg A, Ruther N, Huang X, Wang M, et al. Expression of the c-Met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin’s lymphoma. Haematologica. 2012;97:572–8.

    Article  CAS  Google Scholar 

  38. Murashima A, Shinjo K, Katsushima K, Onuki T, Kondoh Y, Osada H, et al. Identification of a chemical modulator of EZH2-mediated silencing by cell-based high-throughput screening assay. J Biochem. 2019;166:41–50.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was performed as research program with a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (25290048, YK; 19K16752, HT) and the National Cancer Center Research and Development Fund (29-A-3, SI).

Author information

Authors and Affiliations

Authors

Contributions

Conception and design: HT, YK; development of methodology: HT, KS, MS, KK, AM, AI, YK; acquisition of data: HT, KS, MS, KK, SM, AM, AI, MR, SK, HK, HI, TI, SI, YK; analysis and interpretation of data: HT, KS, MS, AM, AI, TI, HI, SI, YK; writing of the paper: HT, YK; administrative, technical, or material support: TI, HI, SI, YK.

Corresponding author

Correspondence to Yutaka Kondo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Totani, H., Shinjo, K., Suzuki, M. et al. Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma. Oncogene 39, 5782–5794 (2020). https://doi.org/10.1038/s41388-020-01393-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-01393-x

This article is cited by

Search

Quick links