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:

Crosstalk between endothelial progenitor cells and HCC through periostin/CCL2/CD36 supports formation of the pro-metastatic microenvironment in HCC

Oncogene volume 43, pages 944–961 (2024)Cite this article

Subjects

Abstract

Metastasis causes most cancer-related deaths, and the role and mechanism of periostin (POSTN) in the metastasis of hepatocellular carcinoma (HCC) remain undiscovered. In this study, DEN and HTVi HCC models were performed in hepatic-specific Postn ablation and Postn knock-in mouse to reveal the role of POSTN in HCC metastasis. Furthermore, POSTN was positively correlated with circulating EPCs level and promoted EPC mobilization and tumour infiltration. POSTN also mediated the crosstalk between HCC and EPCs, which promoted metastasis ability and upregulated CD36 expression in HCC through indirect crosstalk. Chemokine arrays further revealed that hepatic-derived POSTN induced elevated CCL2 expression and secretion in EPCs, and CCL2 promoted prometastatic traits in HCC. Mechanistic studies showed that POSTN upregulated CCL2 expression in EPCs via the αvβ3/ILK/NF-κB pathway. CCL2 further induced CD36 expression via the CCR2/STAT3 pathway by directly binding to the promoter region of CD36. Finally, CD36 was verified to have a prometastatic role in vitro and to be correlated with POSTN expression, metastasis and recurrence in HCC in clinical samples. Our findings revealed that crosstalk between HCC and EPCs is mediated by periostin/CCL2/CD36 signalling which promotes HCC metastasis and emphasizes a potential therapeutic strategy for preventing HCC metastasis.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: In vivo DEN- and HTVi-induced HCC models using liver-specific Postn KO and Postn KI transgenic mice showed that Postn is involved in HCC metastasis.
Fig. 2: POSTN expression is positively correlated with circulating EPCs and mediates the promotion of malignancy in HCC via EPCs.
Fig. 3: CD36 is upregulated in HCC after interaction with EPCs and may be related to HCC metastasis.
Fig. 4: POSTN expression induces migration and tumour infiltration of EPCs and is correlated with CD36 upregulation.
Fig. 5: POSTN mediates the expression and secretion of CCL2 in EPCs, and EPC-derived CCL2 promotes prometastatic traits in HCC cells.
Fig. 6: POSTN promotes CCL2 expression in EPCs via the ILK/NF-κB pathway.
Fig. 7: CCL2 activates STAT3 signalling and further promotes CD36 expression by directly binding to the promoter region of CD36.
Fig. 8: CD36 expression is induced by CCL2 in HCC cell lines and correlated with metastasis and recurrence of HCC.

Similar content being viewed by others

Data availability

All data and materials supporting the findings of this work are available from its supplementary information files and from the corresponding author upon reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3:1683–91.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Llovet J, De Baere T, Kulik L, Haber P, Greten T, Meyer T, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18:293–313.

    Article  CAS  PubMed  Google Scholar 

  4. Wasik A, Ratajczak-Wielgomas K, Badzinski A, Dziegiel P, Podhorska-Okolow M. The role of periostin in angiogenesis and lymphangiogenesis in tumors. Cancers. 2022;14:4225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen G, Wang Y, Zhao X, Xie XZ, Zhao JG, Deng T, et al. A positive feedback loop between Periostin and TGFβ1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation. J Exp Clin Cancer Res. 2021;40:218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, et al. Transcriptional induction of periostin by a sulfatase 2-TGFβ1-SMAD signaling axis mediates tumor angiogenesis in hepatocellular carcinoma. Cancer Res. 2017;77:632–45.

    Article  CAS  PubMed  Google Scholar 

  7. Gillot L, Lebeau A, Baudin L, Pottier C, Louis T, Durré T, et al. Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization. Cell Mol Life Sci. 2022;79:295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xiao H, Zhang Y, Li Z, Liu B, Cui D, Liu F, et al. Periostin deficiency reduces diethylnitrosamine-induced liver cancer in mice by decreasing hepatic stellate cell activation and cancer cell proliferation. J Pathol. 2021;255:212–23.

    Article  CAS  PubMed  Google Scholar 

  9. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008;319:195–8.

    Article  CAS  PubMed  Google Scholar 

  10. Shih Y, Wang M, Zhou J, Peng H, Lee D, Chiu J. Endothelial progenitors promote hepatocarcinoma intrahepatic metastasis through monocyte chemotactic protein-1 induction of microRNA-21. Gut. 2015;64:1132–47.

    Article  CAS  PubMed  Google Scholar 

  11. Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017;20:409–26.

    Article  CAS  PubMed  Google Scholar 

  12. Yu D, Sun X, Qiu Y, Zhou J, Wu Y, Zhuang L, et al. Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin Cancer Res. 2007;13:3814–24.

    Article  CAS  PubMed  Google Scholar 

  13. Ho JW, Pang RW, Lau C, Sun CK, Yu WC, Fan ST, et al. Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatol. 2006;44:836–43.

    Article  CAS  Google Scholar 

  14. Massagué J, Ganesh K. Metastasis-initiating cells and ecosystems. Cancer Discov. 2021;11:971–94.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Castro-Giner F, Aceto N. Tracking cancer progression: from circulating tumor cells to metastasis. Genome Med. 2020;12:31.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ganesh K, Massagué J. Targeting metastatic cancer. Nat Med. 2021;27:34–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z. Lipid metabolism and cancer. J Exp Med. 2021;218:e20201606.

    Article  CAS  PubMed  Google Scholar 

  18. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009;20:72–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pascual G, Avgustinova A, Mejetta S, Martín M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541:41–45.

    Article  CAS  PubMed  Google Scholar 

  20. Ladanyi A, Mukherjee A, Kenny HA, Johnson A, Mitra AK, Sundaresan S, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene. 2018;37:2285–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pfeiler S, Thakur M, Grünauer P, Megens RTA, Joshi U, Coletti R, et al. CD36-triggered cell invasion and persistent tissue colonization by tumor microvesicles during metastasis. FASEB J. 2019;33:1860–72.

    Article  CAS  PubMed  Google Scholar 

  22. Luo X, Zheng E, Wei L, Zeng H, Qin H, Zhang X, et al. The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis. Cell Death Dis. 2021;12:328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Duan F, Wu H, Jia D, Wu W, Ren S, Wang L, et al. O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis. J Hepatol. 2018;68:1191–202.

    Article  CAS  PubMed  Google Scholar 

  24. Robertson CL, Srivastava J, Siddiq A, Gredler R, Emdad L, Rajasekaran D, et al. Genetic deletion of AEG-1 prevents hepatocarcinogenesis. Cancer Res. 2014;74:6184–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. García-Irigoyen O, Latasa MU, Carotti S, Uriarte I, Elizalde M, Urtasun R, 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. Hepatol. 2015;62:166–78.

    Article  Google Scholar 

  26. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatol. 2004;39:1517–24.

    Article  CAS  Google Scholar 

  27. Lei MML, Leung CON, Lau EYT, Leung RWH, Ma VWS, Tong M, et al. SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression. JHEP Rep. 2023;5:100604.

    Article  PubMed  Google Scholar 

  28. Wang Y, Yu H, Shan Y, Tao C, Wu F, Yu Z, 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 Exp Clin Cancer Res. 2016;35:65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Suresh A, Biswas A, Perumal S, Khurana S. Periostin and integrin signaling in stem cell regulation. Adv Exp Med Biol. 2019;1132:163–76.

    Article  CAS  PubMed  Google Scholar 

  30. Ma Z, Zhao X, Deng M, Huang Z, Wang J, Wu Y, et al. Bone marrow mesenchymal stromal cell-derived periostin promotes B-ALL progression by modulating CCL2 in Leukemia Cells. Cell Rep. 2019;26:1533–43.e4.

    Article  CAS  PubMed  Google Scholar 

  31. Lv Y, Wang W, Jia WD, Sun QK, Li JS, Ma JL, et al. High-level expression of periostin is closely related to metastatic potential and poor prognosis of hepatocellular carcinoma. Med Oncol. 2013;30:385.

    Article  PubMed  Google Scholar 

  32. Wang Z, An J, Zhu D, Chen H, Lin A, Kang J, et al. Periostin: an emerging activator of multiple signaling pathways. J Cell Commun Signal. 2022;16:515–30.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang R, Lin XH, Ma M, Chen J, Chen J, Gao DM, et al. Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition. J Transl Med. 2018;16:302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Krishna Priya S, Nagare RP, Sneha VS, Sidhanth C, Bindhya S, Manasa P, et al. Tumour angiogenesis-origin of blood vessels. Int J Cancer. 2016;139:729–35.

    Article  CAS  PubMed  Google Scholar 

  35. Ling CC, Ng KT, Shao Y, Geng W, Xiao JW, Liu H, et al. Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth. J Hepatol. 2014;60:103–9.

    Article  CAS  PubMed  Google Scholar 

  36. Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer. 2002;2:826–35.

    Article  CAS  PubMed  Google Scholar 

  37. Rafii S, Meeus S, Dias S, Hattori K, Heissig B, Shmelkov S, et al. Contribution of marrow-derived progenitors to vascular and cardiac regeneration. Semin Cell Dev Biol. 2002;13:61–7.

    Article  CAS  PubMed  Google Scholar 

  38. Wang G, Wen B, Deng Z, Zhang Y, Kolesnichenko O, Ustiyan V, et al. Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. Nat Commun. 2022;13:2080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zarychta E, Ruszkowska-Ciastek B, Bielawski K, Rhone P. Stromal cell-derived factor 1α (SDF-1α) in invasive breast cancer: associations with vasculo-angiogenic factors and prognostic significance. Cancers. 2021;13:1952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vanharanta S, Massagué J. Origins of metastatic traits. Cancer Cell. 2013;24:410–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168:670–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jiang M, Wu N, Xu B, Chu Y, Li X, Su S, et al. Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis. Theranostics. 2019;9:5359–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nath A, Li I, Roberts LR, Chan C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci Rep. 2015;5:14752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Martin-Perez M, Urdiroz-Urricelqui U, Bigas C, Benitah S. The role of lipids in cancer progression and metastasis. Cell Metab. 2022;34:1675–99.

    Article  CAS  PubMed  Google Scholar 

  45. Aoki T, Kinoshita J, Munesue S, Hamabe-Horiike T, Yamaguchi T, Nakamura Y, et al. Hypoxia-induced CD36 expression in gastric cancer cells promotes peritoneal metastasis via fatty acid uptake. Ann Surg Oncol. 2023;30:3125–36.

    Article  PubMed  Google Scholar 

  46. Yang P, Qin H, Li Y, Xiao A, Zheng E, Zeng H, et al. CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat Commun. 2022;13:5782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. 2016;7:28697–710.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Yoshimura T. The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? Cell Mol Immunol. 2018;15:335–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang WW, Ang SF, Kumar R, Heah C, Utama A, Tania NP, et al. Identification of serum monocyte chemoattractant protein-1 and prolactin as potential tumor markers in hepatocellular carcinoma. PloS One. 2013;8:e68904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut. 2017;66:157–67.

    Article  CAS  PubMed  Google Scholar 

  51. Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 2018;27:136–50.e5.

    Article  CAS  PubMed  Google Scholar 

  52. Sp N, Kang DY, Kim DH, Park JH, Lee HG, Kim HJ, et al. Nobiletin inhibits CD36-dependent tumor angiogenesis, migration, invasion, and sphere formation through the Cd36/Stat3/Nf-Κb signaling axis. Nutrients. 2018;10:772.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475:222–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Wenzhou Municipal Science and Technology Bureau (Y2020153), National Natural Science Foundation of China (81772628, 81703310, 82072685), Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumour and Bioengineering, and the Research Foundation of National Health Commission of China–Major Medical and Health Technology Project for Zhejiang Province (WKJ-ZJ-1706).

Author information

Author notes

  1. These authors contributed equally: Tuo Deng, Jungang Zhao, Yifan Tong.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Tuo Deng, Jungang Zhao, Yifan Tong, Ziyan Chen, Bangjie He, Jiacheng Li, Bo Chen, Rizhao Li, Liming Deng, Haitao Yu, Baofu Zhang, Tan Zhang, Zhehao Shi, Yunfeng Shan, Zhengping Yu, Yuepeng Jin & Gang Chen

  2. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Tuo Deng, Jungang Zhao, Yifan Tong, Ziyan Chen, Bangjie He, Jiacheng Li, Bo Chen, Rizhao Li, Liming Deng, Haitao Yu, Baofu Zhang, Tan Zhang, Zhehao Shi, Yunfeng Shan, Zhengping Yu, Yuepeng Jin, Jinglin Xia & Gang Chen

  3. The Second Affiliated Hospital, Department of General Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China

    Liming Deng

  4. Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Boyang Gao & Junyan Jiang

  5. Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Yi Wang

  6. Liver Cancer Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, China

    Jinglin Xia & Gang Chen

  7. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jinglin Xia

Authors
  1. Tuo Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jungang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yifan Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ziyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bangjie He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiacheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rizhao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Liming Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Haitao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Baofu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhehao Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Boyang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Junyan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yunfeng Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Zhengping Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yuepeng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jinglin Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Gang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GC, JLX and YW conceived and designed this research; TD, JGZ and YFT performed most of the experiments and summarized the results; ZYC, BJH and JCL performed some experiments and provided the data, BC, JYJ and BYG analysed the data; LMD, HTY, BFZ, TZ, ZHS, YFS and ZPY contributed reagents/materials/analysis tools; TD wrote the original manuscript, RZL and YPJ revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yuepeng Jin, Yi Wang, Jinglin Xia or Gang Chen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Study approval

All experiments involving animals were approved by the Animal Care and Use Committee of the First Affiliated Hospital of Wenzhou Medical University and were performed in accordance with the approved protocols. The HCC tumour samples, paraffin sections and blood samples used in the research were obtained from the First Affiliated Hospital of Wenzhou Medical University, and experiments involving human-derived samples were conducted with the approval of the ethics committee of the First Affiliated Hospital of Wenzhou Medical University. All patients provided written informed consent.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, T., Zhao, J., Tong, Y. et al. Crosstalk between endothelial progenitor cells and HCC through periostin/CCL2/CD36 supports formation of the pro-metastatic microenvironment in HCC. Oncogene 43, 944–961 (2024). https://doi.org/10.1038/s41388-024-02960-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-02960-2

Search

Advanced search

Quick links