Top

World Journal of Surgical Oncology

Published in:

Open Access 01-12-2018 | Research

M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway

Authors: Rong-Rong Yao, Jing-Huan Li, Rui Zhang, Rong-Xin Chen, Yan-Hong Wang

Published in: World Journal of Surgical Oncology | Issue 1/2018

Abstract

Background

M2-polarized macrophages are tumor-associated-macrophages (TAMs), which are important contents of tumor-infiltrating immune cells. Toll-like receptor 4 (TLR4) is a molecular biomarker of tumor aggressiveness and poor prognosis. Toll-like receptors (TLRs) have important roles in the immune system and M2-polarized macrophages. However, the effects of TLR4 on M2-polarized macrophages in hepatocellular carcinoma (HCC) are unknown. Here, TLR4 expressed on HCC cells mediates the pro-tumor effects and mechanisms of M2-polarized macrophages.

Methods

THP-1 cells were induced to differentiate into M2-like macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the HCC cell lines SMMC-7721 and MHCC97-H cultured in conditioned medium from M2-like macrophages (M2-CM) to investigate the migration potential of HCC cells and epithelial-mesenchymal transition (EMT)-associated molecular genetics. Signaling pathways that mediated M2-CM-promoted HCC migration were detected using western blotting.

Results

HCC cells cultured with M2-CM displayed a fibroblast-like morphology, an increased metastatic capability, and expression of EMT markers. TLR4 expression was markedly increased in M2-CM-treated HCC cells. TLR4 overexpression promoted HCC cell migration, and a TLR4-neutralizing antibody markedly inhibited HCC EMT in cells cultured with M2-CM. Furthermore, the TLR4/(signal transducer and activator of transcription 3 (STAT3) signaling pathway contributed to the effects of M2-CM on HCC cells.

Conclusions

Taken together, M2-polarized macrophages facilitated the migration and EMT of HCC cells via the TLR4/STAT3 signaling pathway, suggesting that TLR4 may be a novel therapeutic target. These results improve our understanding of M2-polarized macrophages.

Available only for authorised users

Yong KJ, Gao C, Lim JS, Yan B, Yang H, Dimitrov T, et al. Oncofetal Gene SALL4 in Aggressive Hepatocellular carcinoma. N Engl J Med. 2016;368(24):2266–76. https://doi.org/10.1056/NEJMoa1300297.CrossRef

Hernandez-Gea V, Toffanin S, Friedman SL, et al. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144:512–27. https://doi.org/10.1053/j.gastro.2013.01.002.CrossRefPubMedPubMedCentral

Fan QM, Jing YY, Yu GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2014;352:160–8. https://doi.org/10.1016/j.canlet.2014.05.008.CrossRefPubMed

X. Fu, H. Shi and Y. Qi, et al.: M2 polarized macrophages induced by CSE promote proliferation, migration, and invasion of alveolar basal epithelial cells. Int Immunopharmacol 28 (2015) 666–74. Doi: https://doi.org/10.1016/j.intimp.2015.07.033.

A. Schmieder, J. Michel and K. Schledzewski, et al.: Differentiation and gene expression profile of tumor-associated macrophages. Semin Cancer Biol 22 (2012) 289–97. Doi: https://doi.org/10.1016/j.semcancer.

X.Z. Ye, S.L. Xu and X.W. Bian, et al.: Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J Immunol 189 (2012) 444–53. Doi: https://doi.org/10.4049/jimmunol.

C.Y. Liu, J.Y. Xu and J.L. Ding, et al.: M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab Invest 93 (2013) 844–54. Doi: https://doi.org/10.1038/labinvest.

Genin M, Clement F, Michiels C, et al. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer. 2015;15:577. https://doi.org/10.1186/s12885-015-1546-9.CrossRefPubMedPubMedCentral

J.B. Jia, W.Q. Wang and Z.Y. Tang, et al.: High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection. Oncologist 15 (2010) 732–43.Doi: https://doi.org/10.1634/theoncologist.2009-0170.

10.

A. Oblak, and R. Jerala: Toll-like receptor 4 activation in cancer progression and therapy. Clin Dev Immunol 2011 (2011) 609579. Doi: https://doi.org/10.1155/2011/609579.

11.

W.T. Liu, Y.Y. Jing and L.X. Wei, et al.: Toll like receptor 4 facilitates invasion and migration as a cancer stem cell marker in hepatocellular carcinoma. Cancer Lett 358 (2015) 136–43.Doi: https://doi.org/10.1016/j.canlet.2014.12.019.

12.

K. Machida, D.E. Feldman, and H. Tsukamoto: TLR4-dependent tumor-initiating stem cell-like cells (TICs) in alcohol-associated hepatocellular carcinogenesis. Adv Exp Med Biol 815 (2015) 131–44. Doi: https://doi.org/10.1007/978-3-319-09614-8_8.

13.

N. Eiro, A. Altadill, L.M. Juarez and F.J. Vizoso, et al.: Toll-like receptors 3, 4 and 9 in hepatocellular carcinoma: Relationship with clinicopathological characteristics and prognosis. Hepatol Res 44 (2014) 769–78. Doi: https://doi.org/10.1111/hepr.12180.

14.

J.W. Tjiu, J.S. Chen and S.H. Jee, et al.: Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol 129 (2009) 1016–25. Doi: https://doi.org/10.1038/jid.2008.310.

15.

Xu H, Lai W, Chu Z, et al. Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner. BMC Cancer. 2014;14:330. https://doi.org/10.1186/1471-2407-14-330.CrossRefPubMedPubMedCentral

16.

C.C. Hsiao, P.H. Chen, Cheng CI and Y.H. Kao, et al.: Toll-like receptor-4 is a target for suppression of proliferation and chemoresistance in HepG2 hepatoblastoma cells. Cancer Lett 368 (2015) 144–52. Doi: https://doi.org/10.1016/j.canlet.2015.08.004.

17.

Jing YY, Han ZP, Wei LX, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012;10:98. https://doi.org/10.1186/1741-7015-10-98.CrossRefPubMedPubMedCentral

18.

D. Capece, M. Fischietti and E. Alesse, et al.: The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int 2013 (2013) 187204. Doi: https://doi.org/10.1155/2013/187204.

19.

S. Wan, E. Zhao and T.H. Welling, et al.: Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147 (2014) 1393–404. Doi: https://doi.org/10.1053/j.gastro.2014.08.039.

20.

Kurahara H, Shinchi H, Takao S, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res. 2011;167:e211–9. https://doi.org/10.1016/j.jss.2009.05.026. Epub 2009 Jun 16CrossRefPubMed

21.

G. Niedobitek, M.H. Barros and D. Al-Sheikhyaqoob, et al.: Tumor-associated macrophages : Function and differentiation. Pathologe 36 (2015) 477–84. Doi: https://doi.org/10.1007/s00292-015-0054-7.

22.

Gulubova M, Ananiev J, Vlaykova T, et al. The density of macrophages in colorectal cancer is inversely correlated to TGF-beta1 expression and patients' survival. J Mol Histol. 2013;44:679–92. https://doi.org/10.1007/s10735-013-9520-9. Epub 2013 Jun 26CrossRefPubMed

23.

J. Gu, R. Sun and Z. Yu, et al.: The influence of TLR4 agonist lipopolysaccharides on hepatocellular carcinoma cells and the feasibility of its application in treating liver cancer. Onco Targets Ther 8 (2015) 2215–25. Doi: https://doi.org/10.2147/OTT.S86536. eCollection 2015.

24.

M. Ikebe, Y. Kitaura and M. Katano, et al.: Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol 100 (2009) 725–31. Doi: https://doi.org/10.1002/jso.21392.

25.

L. Wang, R. Zhu and H. Zhu, et al.: Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci 58 (2013) 2223–36. Doi: https://doi.org/10.1007/s10620-013-2745-3. Epub 2013 Jul 5.

Title: M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway
Authors: Rong-Rong Yao
Jing-Huan Li
Rui Zhang
Rong-Xin Chen
Yan-Hong Wang
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2018
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/s12957-018-1312-y

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Evaluation of the expression and clinical value of lncRNA AC010761.9 in human gastric adenocarcinoma

The change of health-related quality of life after minimally invasive esophagectomy for esophageal cancer: a meta-analysis

LZTS2 promoter hypermethylation: a potential biomarker for the diagnosis and prognosis of laryngeal squamous cell carcinoma

Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer

Development and internal validation of PI-RADs v2-based model for clinically significant prostate cancer

The risk factors for benign small bowel obstruction following curative resection in patients with rectal cancer