Hepatic stellate cells promote angiogenesis of hepatocellular carcinoma by affecting Ang-1/Tie2 axis

doi:10.3877/cma.j.issn.2095-3232.2019.04.021

Abstract

Abstract:

Objective

To investigate the effect and its mechanism of hepatic stellate cells (HSC) on the angiogenesis of liver cancer cells.

Methods

Primary human hepatocellular carcinoma cells (HC), human hematopoietic stem cells (HSC) and human vascular endothelial cells (HVEC) were successfully obtained with collagenase perfusion. The expression levels of angiogenesis-related genes in 3 groups were measured by RT-PCR. The expression levels of angiopoietin-1 (Ang-1) in HSCs activated under different concentrations of TGF-β were measured by RT-PCR and ELISA. The expression levels of Tie2 gene and protein in coculture of HVECs and HSCs were detected by RT-PCR and Western blot. The expression levels of Ang-1 and Tie2 mRNA among different groups were statistically compared by univariate ANOVA and LSD-t test.

Results

The relative expression levels of Ang-1 mRNA in HCs, HSCs and HVECs were 1.6±0.4, 7.6±1.6 and 0.4±0.1, respectively, the expression level in HSCs was the highest (F=94.6, P<0.05). The relative expression levels of Tie2 mRNA were 0.1, 1.3 and 14.4±2.2, respectively, with the highest level in HVECs (F=239.4, P<0.05). With the increasing concentration of TGF-β, the expression of α-SMA and Ang-1 mRNA in HSCs was up-regulated. The same increasing trend was observed in the supernatant of cell culture solution. With the increase of HSC activation, the ability of expressing Tie2 mRNA of HVECs in the co-culture system enhanced, and the ability of inducing Tie2 protein expression of HSCs enhanced, too.

Conclusions

Activated HSC is the main source of Ang-1 in the microenvironment of liver cancer. HSC can effectively promote the angiogenesis of liver cancer probably through the Ang-1/Tie2 axis.

Key words: Carcinoma, hepatocellular, Hepatic stellate cells, Angiopoietin-1, Neovascularization, pathologic

Yang Lin, Yanlong Cao, Hong Qiu, Nan Lin, Jianhua Wu. Hepatic stellate cells promote angiogenesis of hepatocellular carcinoma by affecting Ang-1/Tie2 axis[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2019, 08(04): 370-374.

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References 19

[1]	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2):87-108.
[2]	Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer[J]. Nat Rev Cancer, 2015, 15(11):653-667.
[3]	Coulon S, Heindryckx F, Geerts A, et al. Angiogenesis in chronic liver disease and its complications[J]. Liver Int, 2011, 31(2):146-162.
[4]	Hawighost H, Knapstein PG, Knopp MV, et al. Uterine cervical carcinoma: comparison of standard and pharmacokinetic analysis of time-intensity curves for assessment of tumor angiogenesis and patient survival[J]. Cancer Res, 1998, 58(16):3598-3602.
[5]	Lin N, Chen Z, Lu Y, et al. Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma[J]. Hepatol Res, 2015, 45(3):326-336.
[6]	唐亚军，潘楚芝，卢逸，等．活化态肝星状细胞促进肝癌血管新生的机制[J/CD]．中华肝脏外科手术学电子杂志，2016, 5(5):323-327.
[7]	El-Serag HB. Hepatocellular carcinoma[J]. N Engl J Med, 2011, 365(12):1118-1127.
[8]	Ju MJ, Qiu SJ, Fan J, et al. Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection[J]. Am J Clin Pathol, 2009, 131(4):498-510.
[9]	Song J, Ge Z, Yang X, et al. Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin[J]. Cancer Lett, 2015, 356(2 Pt B):713-720.
[10]	Eveno C, Hainaud P, Rampanou A, et al. Proof of prometastatic niche induction by hepatic stellate cells[J]. J Surg Res, 2015, 194(2):496-504.
[11]	Kalluri R, Zeisberg M. Fibroblasts in cancer[J]. Nat Rev Cancer, 2006, 6(5):392-401.
[12]	Zhao W, Zhang L, Yin Z, et al. Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice[J]. Int J Cancer, 2011, 129(11):2651-2661.
[13]	Zhu B, Lin N, Zhang M, et al. Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma[J]. J Transl Med, 2015(13):365.
[14]	Lund EL, Høg A, Olsen MW, et al. Differential regulation of VEGF, HIF1alpha, and angiopoietin-1, -2, and-4 by hypoxia and ionizing radiation in human glioblastoma[J]. Int J Cancer, 2004, 108(6):833-838.
[15]	Malsonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural agonist for Tie2 that disrupts in vivo angiogenesis[J]. Science, 1997, 277(5322):55-60.
[16]	Huang J, Inoue M, Hasegawa M, et al. Sendai viral vector mediated angiopoietin-1 gene transfer for experimental ischemic limb disease[J]. Angiogenesis, 2009, 12(3):243-249.
[17]	Scharpfenecker M, Fiedler U, Reiss Y, et al. The Tie2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism[J]. J Cell Sci, 2005, 118(Pt 4):771-780.
[18]	Lee SW, Kim WJ, Jun HO, et al. Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2[J]. Int J Mol Med, 2009, 23(2):279-284.
[19]	Reiss Y, Knedla A, Tal AO, et al. Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2[J]. J Pathol, 2009, 217(4):571-580.

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