High expression of endothelial progenitor cell‑induced angiogenic markers is associated with bile acid levels in HCC

Chen,Jiang‑Long; Wang,Long; Li,Rong; Jiao,Ying‑Fu; Yu,Wei‑Feng

doi:10.3892/ol.2020.11815

High expression of endothelial progenitor cell‑induced angiogenic markers is associated with bile acid levels in HCC

Authors:
- Jiang‑Long Chen
- Long Wang
- Rong Li
- Ying‑Fu Jiao
- Wei‑Feng Yu
View Affiliations

Affiliations: Department of General Surgery, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200062, P.R. China, Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China, Department of Pathology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200433, P.R. China, Department of Anesthesiology, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
Published online on: July 6, 2020 https://doi.org/10.3892/ol.2020.11815
Pages: 2729-2738
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Endothelial progenitor cell (EPC)‑induced angiogenesis activity is enhanced in hepatocellular carcinoma (HCC); however, the contributing factors remain unknown. The present study aimed to investigate the factors influencing the number of EPCs and circulating progenitor cells (CPCs), as well as the expression levels of vascular endothelial growth factor receptor 2 (VEGFR‑2) and CD34, in patients with HCC. The expression levels of VEGFR‑2 and CD34 were assessed in 72 HCC tumor and matched adjacent tissue microarrays by immunohistochemistry. The associations between VEGFR‑2 or CD34 expression in tumors, clinicopathological characteristics and overall survival rates were analyzed. The number of EPCs and CPCs were analyzed in the peripheral blood of patients with HCC. In this study, high expression levels of VEGFR‑2 and CD34 were detected in the tumor tissues of 41 (56.9%) and 44 (61.1%) patients, respectively. VEGFR‑2 expression was significantly associated with tumor size (P<0.001), bile acid level (P=0.014) and α‑fetoprotein level (P=0.011). However, CD34 expression was associated with tumor size (P=0.009), recrudescence (P<0.001) and bile acid (P=0.009). Next, the expression levels of VEGFR‑2 and CD34 in tumor and adjacent tissues were compared according to the bile acid level. VEGFR‑2 and CD34 expression levels were both higher in the high bile acid group, whereas expression levels of the markers were higher in adjacent tissues compared with tumor tissues. Kaplan‑Meier curve analysis identified that patients with low CD34 expression had a longer overall survival compared with patients with high CD34 expression (P=0.029). Multivariate analysis also indicated that both VEGFR‑2 (P=0.020) and CD34 (P=0.035) were independent prognostic risk factors. Moreover, flow cytometry demonstrated that the number of EPCs and CPCs was negatively related with the bile acid levels in patients with HCC. In conclusion, in patients with HCC, bile acid promotes EPC‑induced angiogenesis. Furthermore, EPCs and CPCs may be activated by bile acid in tumors but are more so in adjacent tissues.

View Figures

View References

1	St Croix BD, Rak JW and Kerbel RS: Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anticancer Drugs. 6:3–18. 1995. View Article : Google Scholar : PubMed/NCBI
2	Hervey-Jumper SL, Garton HJL, Lau D, Altshuler D, Quint DJ, Robertson PL, Muraszko KM and Maher CO: Differences in vascular endothelial growth factor receptor expression and correlation with the degree of enhancement in medulloblastoma. J Neurosurg Pediatr. 14:121–128. 2014. View Article : Google Scholar : PubMed/NCBI
3	Li S, Xu HX, Wu CT, Wang WQ, Jin W, Gao HL, Li H, Zhang SR, Xu JZ, Qi ZH, et al: Angiogenesis in pancreatic cancer: Current research status and clinical implications. Angiogenesis. 22:15–36. 2019. View Article : Google Scholar : PubMed/NCBI
4	Folkman J: What is the evidence that tumors are angiogenesis dependent. J Natl Cancer Inst. 82:4–6. 1990. View Article : Google Scholar : PubMed/NCBI
5	Viallard C and Larrivee B: Tumor angiogenesis and vascular normalization: Alternative therapeutic targets. Angiogenesis. 20:409–426. 2017. View Article : Google Scholar : PubMed/NCBI
6	Peters EB: Endothelial progenitor cells for the vascularization of engineered tissues. Tissue Eng Part B Rev. 24:1–24. 2018. View Article : Google Scholar : PubMed/NCBI
7	Mandraffino G and Saitta A: Endothelial and circulating progenitor cells: Between diseases and therapies. Curr Med Chem. 25:4476–4477. 2018. View Article : Google Scholar : PubMed/NCBI
8	Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, et al: Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: A systematic analysis for the global burden of disease study 2017. Lancet. 394:1145–1158. 2019. View Article : Google Scholar : PubMed/NCBI
9	Zhu AX, Duda DG, Sahani DV and Jain RK: HCC and angiogenesis: Possible targets and future directions. Nat Rev Clin Oncol. 8:292–301. 2011. View Article : Google Scholar : PubMed/NCBI
10	Rafii S and Lyden D: Cancer. A few to flip the angiogenic switch. Science. 319:163–164. 2008. View Article : Google Scholar : PubMed/NCBI
11	Poon RT, Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C and Wong J: Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: Is it justified? Ann Surg. 236:602–611. 2002. View Article : Google Scholar : PubMed/NCBI
12	Ho JW, Pang RW, Lau C, Sun CK, Yu WC, Fan ST and Poon RT: Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatology. 44:836–843. 2006. View Article : Google Scholar : PubMed/NCBI
13	Sieghart W, Fellner S, Reiberger T, Ulbrich G, Ferlitsch A, Wacheck V and Peck-Radosavljevic M: Differential role of circulating endothelial progenitor cells in cirrhotic patients with or without hepatocellular carcinoma. Dig Liver Dis. 41:902–906. 2009. View Article : Google Scholar : PubMed/NCBI
14	Yu D, Sun X, Qiu Y, Zhou J, Wu Y, Zhuang L, Chen J and Ding Y: Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin Cancer Res. 13:3814–3824. 2007. View Article : Google Scholar : PubMed/NCBI
15	Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, Daenen LG, Man S, Xu P, Emmenegger U, et al: Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: Implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 14:263–273. 2008. View Article : Google Scholar : PubMed/NCBI
16	Li CX, Shao Y, Ng KT, Liu XB, Ling CC, Ma YY, Geng W, Fan ST, Lo CM and Man K: FTY720 suppresses liver tumor metastasis by reducing the population of circulating endothelial progenitor cells. PLoS One. 7:e323802012. View Article : Google Scholar : PubMed/NCBI
17	Lee ES, Han EM, Kim YS, Shin BK, Kim CH, Kim HK, Won NH, Yeom BW, Kim I and Leong ASY: Occurrence of c-kit+ tumor cells in hepatitis B virus-associated hepatocellular carcinoma. Am J Clin Pathol. 124:31–36. 2005. View Article : Google Scholar : PubMed/NCBI
18	Yamada S, Takashina Y, Watanabe M, Nagamine R, Saito Y, Kamada N and Saito H: Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget. 9:9925–9939. 2018. View Article : Google Scholar : PubMed/NCBI
19	Liu N, Feng H, Lv Y, Liu Q, Deng J, Xia Y, Guo C and Zhou Y: Role of bile acids in the diagnosis and progression of liver cirrhosis: A prospective observational study. Exp Ther Med. 18:4058–4066. 2019.PubMed/NCBI
20	Wu WB, Chen YY, Zhu B, Peng XM, Zhang SW and Zhou ML: Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice. Biochimie. 115:86–92. 2015. View Article : Google Scholar : PubMed/NCBI
21	Liao M, Zhao J, Wang T, Duan J, Zhang Y and Deng X: Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells. Mol Cancer. 10:442011. View Article : Google Scholar : PubMed/NCBI
22	Wang C, Yang M, Zhao J, Li X, Xiao X, Zhang Y, Jin X and Liao M: Bile salt (glycochenodeoxycholate acid) induces cell survival and chemoresistance in hepatocellular carcinoma. J Cell Physiol. 234:10899–10906. 2019. View Article : Google Scholar : PubMed/NCBI
23	Cho JG, Lee JH, Hong SH, Lee HN, Kim CM, Kim SY, Yoon KJ, Oh BJ, Kim JH, Jung SY, et al: Tauroursodeoxycholic acid, a bile acid, promotes blood vessel repair by recruiting vasculogenic progenitor cells. Stem Cells. 33:792–805. 2015. View Article : Google Scholar : PubMed/NCBI
24	Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM and Asahara T: Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 5:434–438. 1999. View Article : Google Scholar : PubMed/NCBI
25	Rafii S: Circulating endothelial precursors: Mystery, reality, and promise. J Clin Invest. 105:17–19. 2000. View Article : Google Scholar : PubMed/NCBI
26	Carmeliet P and Jain R: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
27	Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 20:4368–4380. 2002. View Article : Google Scholar : PubMed/NCBI
28	Ferrara N, Hillan KJ, Gerber HP and Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 3:391–400. 2004. View Article : Google Scholar : PubMed/NCBI
29	Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, et al: Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 104:3360–3365. 2007. View Article : Google Scholar : PubMed/NCBI
30	Zhao S, Wang M, Yang Z, Tan K, Zheng D, Du X and Liu L: Comparison between child-pugh score and albumin-bilirubin grade in the prognosis of patients with HCC after liver resection using time-dependent ROC. Ann Transl Med. 8:5392020. View Article : Google Scholar : PubMed/NCBI
31	Glaser S, Onori P, Gaudio E, Ueno Y, Pannarale L, Franchitto A, Francis H, Mancinelli R, Carpino G, Venter J, et al: Taurocholic acid prevents biliary damage induced by hepatic artery ligation in cholestatic rats. Dig Liver Dis. 42:709–717. 2010. View Article : Google Scholar : PubMed/NCBI
32	Nakamura K, Zen Y, Sato Y, Kozaka K, Matsui O, Harada K and Nakanuma Y: Vascular endothelial growth factor, its receptor Flk-1, and hypoxia inducible factor-1alpha are involved in malignant transformation in dysplastic nodules of the liver. Hum Pathol. 38:1532–1546. 2007. View Article : Google Scholar : PubMed/NCBI
33	Iavarone M, Lampertico P, Iannuzzi F, Manenti E, Donato MF, Arosio E, Bertolini F, Primignani M, Sangiovanni A and Colombo M: Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma. J Viral Hepat. 14:133–139. 2007. View Article : Google Scholar : PubMed/NCBI
34	Jia JB, Zhuang PY, Sun HC, Zhang JB, Zhang W, Zhu XD, Xiong YQ, Xu HX and Tang ZY: Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival. J Cancer Res Clin Oncol. 135:847–854. 2009. View Article : Google Scholar : PubMed/NCBI
35	Huang J, Zhang X, Tang Q, Zhang F, Li Y, Feng Z and Zhu J: Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J Clin Pathol. 64:343–348. 2011. View Article : Google Scholar : PubMed/NCBI
36	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
37	Wang H, Chen K, Niu G and Chen X: Site-specifically biotinylated VEGF(121) for nearinfrared fluorescence imaging of tumor angiogenesis. Mol Pharm. 6:285–294. 2009. View Article : Google Scholar : PubMed/NCBI
38	Giannelli G, Sgarra C, Porcelli L, Azzariti A, Antonaci S and Paradiso A: EGFR and VEGFR as potential target for biological therapies in HCC cells. Cancer Lett. 262:257–264. 2008. View Article : Google Scholar : PubMed/NCBI
39	Tsuji N, Ishiguro S, Sasaki Y and Kudo M: CD34 expression in noncancerous liver tissue predicts multicentric recurrence of hepatocellular carcinoma. Dig Dis. 31:467–471. 2013. View Article : Google Scholar : PubMed/NCBI
40	Yang ZF and Poon RT: Vascular changes in hepatocellular carcinoma. Anat Rec (Hoboken). 291:721–734. 2008. View Article : Google Scholar : PubMed/NCBI
41	Segatelli V, de Oliveira EC, Boin IF, Ataide EC and Escanhoela CA: Evaluation and comparison of microvessel density using the markers CD34 and CD105 in regenerative nodules, dysplastic nodules and hepatocellular carcinoma. Hepatol Int. 8:260–265. 2014.PubMed/NCBI
42	Zhu X, Zhou H, Luo J, Cui Y, Li H, Zhang W, Fang F, Li Q and Zhang T: Different but synergistic effects of bone marrow-derived VEGFR2+ and VEGFR2−CD45+ cells during hepatocellular carcinoma progression. Oncol Lett. 13:63–68. 2017. View Article : Google Scholar : PubMed/NCBI
43	Fürstenberger G, von Moos R, Lucas R, Thürlimann B, Senn HJ, Hamacher J and Boneberg EM: Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br J Cancer. 94:524–531. 2006. View Article : Google Scholar : PubMed/NCBI
44	Zahran AM, Abdel-Rahim MH, Refaat A, Sayed M, Othman MM, Khalak LMR and Hetta HF: Circulating hematopoietic stem cells, endothelial progenitor cells and cancer stem cells in hepatocellular carcinoma patients: Contribution to diagnosis and prognosis. Acta Oncol. 59:33–39. 2020. View Article : Google Scholar : PubMed/NCBI