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

doi:10.1038/s41388-024-02960-2

. 2024 Mar;43(13):944-961.

doi: 10.1038/s41388-024-02960-2. Epub 2024 Feb 13.

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

Tuo Deng^#^{1

2}, Jungang Zhao^#^{1

2}, Yifan Tong^#^{1

2}, Ziyan Chen^{1

2}, Bangjie He^{1

2}, Jiacheng Li^{1

2}, Bo Chen^{1

2}, Rizhao Li^{1

2}, Liming Deng^{1

2

3}, Haitao Yu^{1

2}, Baofu Zhang^{1

2}, Tan Zhang^{1

2}, Zhehao Shi^{1

2}, Boyang Gao⁴, Junyan Jiang⁴, Yunfeng Shan^{1

2}, Zhengping Yu^{1

2}, Yuepeng Jin^{5

6}, Yi Wang⁷, Jinglin Xia^{8

9

10}, Gang Chen^{11

12

13}

Affiliations

¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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.
³ The Second Affiliated Hospital, Department of General Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁴ Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁵ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. quiet1981@163.com.
⁶ 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. quiet1981@163.com.
⁷ Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China. wang.yi@wmu.edu.cn.
⁸ 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. xiajinglin@fudan.edu.cn.
⁹ Liver Cancer Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, China. xiajinglin@fudan.edu.cn.
¹⁰ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. xiajinglin@fudan.edu.cn.
¹¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. chen.gang@wmu.edu.cn.
¹² 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. chen.gang@wmu.edu.cn.
¹³ Liver Cancer Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, China. chen.gang@wmu.edu.cn.

^# Contributed equally.

PMID: 38351345
DOI: 10.1038/s41388-024-02960-2

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

Tuo Deng et al. Oncogene. 2024 Mar.

. 2024 Mar;43(13):944-961.

doi: 10.1038/s41388-024-02960-2. Epub 2024 Feb 13.

Authors

Affiliations

¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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.
³ The Second Affiliated Hospital, Department of General Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁴ Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁵ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. quiet1981@163.com.
⁶ 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. quiet1981@163.com.
⁷ Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China. wang.yi@wmu.edu.cn.
⁸ 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. xiajinglin@fudan.edu.cn.
⁹ Liver Cancer Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, China. xiajinglin@fudan.edu.cn.
¹⁰ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. xiajinglin@fudan.edu.cn.
¹¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. chen.gang@wmu.edu.cn.
¹² 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. chen.gang@wmu.edu.cn.
¹³ Liver Cancer Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, China. chen.gang@wmu.edu.cn.

^# Contributed equally.

PMID: 38351345
DOI: 10.1038/s41388-024-02960-2

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.

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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. - PubMed - DOI
1. 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. - PubMed - PMC - DOI
1. 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. - PubMed - DOI
1. 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. - PubMed - PMC - DOI
1. 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. - PubMed - PMC - DOI

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[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. - PubMed - DOI

[2] 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. - PubMed - DOI

[3] 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. - PubMed - PMC - DOI

[4] 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. - PubMed - PMC - DOI

[5] 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. - PubMed - DOI

[6] 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. - PubMed - DOI

[7] 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. - PubMed - PMC - DOI

[8] 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. - PubMed - PMC - DOI

[9] 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. - PubMed - PMC - DOI

[10] 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. - PubMed - PMC - DOI

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

Affiliations

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

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