Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
August-2018 Volume 16 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
August-2018 Volume 16 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma

  • Authors:
    • Wei Li
    • Yong‑Bin Jian
  • View Affiliations / Copyright

    Affiliations: Interventional Medical Center, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266555, P.R. China, Department of Interventional Radiology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 529-536
    |
    Published online on: May 30, 2018
       https://doi.org/10.3892/etm.2018.6235
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Hepatocellular carcinoma (HCC) accounts for many cases of cancer-associated mortality. Tumor necrosis factor (TNF)-α is a key mediator of tumor‑promoting inflammation. It has been demonstrated that anti‑TNF‑α treatments have preclinical benefits for multiple types of cancer, however their potential for treating HCC remains unclear. Through fluorescence‑activated cell sorter analysis and enzyme‑linked immunosorbent assay, the results of the current study indicated that TNF‑α was strongly expressed in HCC tissues and the HCC cell lines HepG2 and Hep3B. In vitro, anti‑TNF‑α antibodies (infliximab and etanercept) decreased HCC cell viability via antibody‑dependent cell‑mediated cytotoxicity and complement‑dependent cytotoxicity effects. Infliximab treatment also significantly increased apoptosis in HepG2 and Hep3B cells compared with controls (P<0.001 and P<0.05, respectively). In vivo, anti‑TNF‑α treatment delayed HCC progression as indicated by the significantly prolonged survival time in an HCC xenograft mouse model (P=0.0009). Further analyses revealed that anti‑TNF‑α treatment significantly decreased the expression of pro‑inflammatory cytokines, including TNF‑α (P<0.01), interleukin (IL)‑1β (P<0.05), IL‑6 (P<0.05) and IL‑17 (P<0.05) and induced apoptosis in HCC tumors. The results of the current study suggest that TNF‑α is a potential target for novel therapeutic strategies to treat HCC. Anti‑TNF‑α treatments compromised HCC tumor progression by inducing cell death and decreasing levels of pro‑inflammatory cytokines.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

World Health Organization (WHO): Cancer Fact Sheet. 2017

2 

Zhang Y, Ren JS, Shi JF, Li N, Wang YT, Qu C, Zhang Y and Dai M: International trends in primary liver cancer incidence from 1973 to 2007. BMC Cancer. 15:942015. View Article : Google Scholar : PubMed/NCBI

3 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Lin MV, King LY and Chung RT: Hepatitis C virus-associated cancer. Annu Rev Pathol. 10:345–370. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Markowitz GJ, Michelotti GA, Diehl AM and Wang XF: Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma. Sci Bull (Beijing). 60:762–772. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Fushiya N, Koike K, Nishino H and Tajiri H: Comparison of the prognostic value of inflammation-based prognostic scores in patients with hepatocellular carcinoma. Br J Cancer. 107:988–993. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Proctor MJ, Morrison DS, Talwar D, Balmer SM, O'Reilly DS, Foulis AK, Horgan PG and McMillan DC: An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: A glasgow inflammation outcome study. Br J Cancer. 104:726–734. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Lasry A and Ben-Neriah Y: Senescence-associated inflammatory responses: Aging and cancer perspectives. Trends Immunol. 36:217–228. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Xu J, Yin Z, Cao S, Gao W, Liu L, Yin Y, Liu P and Shu Y: Systematic review and meta-analysis on the association between IL-1B polymorphisms and cancer risk. PLoS One. 8:e636542013. View Article : Google Scholar : PubMed/NCBI

10 

Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Chu WM: Tumor necrosis factor. Cancer Lett. 328:222–225. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Engelmann H, Holtmann H, Brakebusch C, Avni YS, Sarov I, Nophar Y, Hadas E, Leitner O and Wallach D: Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem. 265:14497–14504. 1990.PubMed/NCBI

13 

Chu WM: Tumor necrosis factor. Cancer Lett. 328:222–225. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Mocellin S, Rossi CR, Pilati P and Nitti D: Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev. 16:35–53. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Zins K, Abraham D, Sioud M and Aharinejad S: Colon cancer cell-derived tumor necrosis factor-alpha mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway. Cancer Res. 67:1038–1045. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Hagemann T, Robinson SC, Schulz M, Trümper L, Balkwill FR and Binder C: Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 25:1543–1549. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Egberts JH, Cloosters V, Noack A, Schniewind B, Thon L, Klose S, Kettler B, von Forstner C, Kneitz C, Tepel J, et al: Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 68:1443–1450. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Ferrajoli A, Keating MJ, Manshouri T, Giles FJ, Dey A, Estrov Z, Koller CA, Kurzrock R, Thomas DA, Faderl S, et al: The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia. Blood. 100:1215–1219. 2002.PubMed/NCBI

19 

Aroucha DC, do Carmo RF, Moura P, Silva JL, Vasconcelos LR, Cavalcanti MS, Muniz MT, Aroucha ML, Siqueira ER, Cahú GG, et al: High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C. Cytokine. 62:421–425. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Wang YY, Lo GH, Lai KH, Cheng JS, Lin CK and Hsu PI: Increased serum concentrations of tumor necrosis factor-alpha are associated with disease progression and malnutrition in hepatocellular carcinoma. J Chin Med Assoc. 66:593–598. 2003.PubMed/NCBI

21 

Avrămescu CS, Comănescu V, Popescu SN, Turculeanu A, Bălăşoiu M, Popescu CF and Lungulescu M: Correlations among the serum levels of some interleukins and the histopathological aspects in chronic viral hepatitis C. Rom J Morphol Embryol. 49:57–62. 2008.PubMed/NCBI

22 

Yu M, Zhou X, Niu L, Lin G, Huang J, Zhou W, Gan H, Wang J, Jiang X, Yin B and Li Z: Targeting transmembrane TNF-α suppresses breast cancer growth. Cancer Res. 73:4061–4074. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Castello G, Scala S, Palmieri G, Curley SA and Izzo F: HCV-related hepatocellular carcinoma: From chronic inflammation to cancer. Clin Immunol. 134:237–250. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Bulló M, García-Lorda P, Megias I and Salas-Salvadó J: Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res. 11:525–531. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Carswell EA, Old LJ, Kassel RL, Green S, Fiore N and Williamson B: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 72:3666–3670. 1975. View Article : Google Scholar : PubMed/NCBI

27 

Balkwill F: Tumour necrosis factor and cancer. Nat Rev Cancer. 9:361–371. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Kulbe H, Thompson R, Wilson JL, Robinson S, Hagemann T, Fatah R, Gould D, Ayhan A and Balkwill F: The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res. 67:585–592. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Zhou X, Zhou S, Li B, Li Q, Gao L, Li D, Gong Q, Zhu L, Wang J, Wang N, et al: Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy. Blood. 126:1433–1442. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, Coussens LM and DeClerck YA: Tumor microenvironment complexity: Emerging roles in cancer therapy. Cancer Res. 72:2473–2480. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Whiteside TL: The tumor microenvironment and its role in promoting tumor growth. Oncogene. 27:5904–5912. 2008. View Article : Google Scholar : PubMed/NCBI

32 

Trédan O, Galmarini CM, Patel K and Tannock IF: Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 99:1441–1454. 2007. View Article : Google Scholar : PubMed/NCBI

33 

Ostman A: The tumor microenvironment controls drug sensitivity. Nat Med. 18:1332–1334. 2012. View Article : Google Scholar : PubMed/NCBI

34 

Zhao X, He Y, Gao J, Fan L, Li Z, Yang G and Chen H: Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer. PLoS One. 8:e591022013. View Article : Google Scholar : PubMed/NCBI

35 

Zhao X, He Y and Chen H: Autophagic tumor stroma: Mechanisms and roles in tumor growth and progression. Int J Cancer. 132:1–8. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Bozcuk H, Uslu G, Samur M, Yildiz M, Ozben T, Ozdoğan M, Artaç M, Altunbaş H, Akan I and Savaş B: Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. Cytokine. 27:58–65. 2004. View Article : Google Scholar : PubMed/NCBI

37 

Karayiannakis AJ, Syrigos KN, Polychronidis A, Pitiakoudis M, Bounovas A and Simopoulos K: Serum levels of tumor necrosis factor-alpha and nutritional status in pancreatic cancer patients. Anticancer Res. 21:1355–1358. 2001.PubMed/NCBI

38 

Adams GP and Weiner LM: Monoclonal antibody therapy of cancer. Nat Biotechnol. 23:1147–1157. 2005. View Article : Google Scholar : PubMed/NCBI

39 

Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, To K, Harashima S, Hatta N and Harada M: Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: Comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum. 58:1248–1257. 2008. View Article : Google Scholar : PubMed/NCBI

40 

Horiuchi T, Mitoma H, Harashima SI, Tsukamoto H and Shimoda T: Transmembrane TNF-alpha: Structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). 49:1215–1228. 2010. View Article : Google Scholar : PubMed/NCBI

41 

Sethi G, Sung B and Aggarwal BB: TNF: A master switch for inflammation to cancer. Front Biosci. 13:5094–5107. 2008. View Article : Google Scholar : PubMed/NCBI

42 

Zhou C, Nitschke AM, Xiong W, Zhang Q, Tang Y, Bloch M, Elliott S, Zhu Y, Bazzone L, Yu D, et al: Proteomic analysis of tumor necrosis factor-alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype. Breast Cancer Res. 10:R1052008. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Li W and Jian YB: Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma. Exp Ther Med 16: 529-536, 2018.
APA
Li, W., & Jian, Y. (2018). Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma. Experimental and Therapeutic Medicine, 16, 529-536. https://doi.org/10.3892/etm.2018.6235
MLA
Li, W., Jian, Y."Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma". Experimental and Therapeutic Medicine 16.2 (2018): 529-536.
Chicago
Li, W., Jian, Y."Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma". Experimental and Therapeutic Medicine 16, no. 2 (2018): 529-536. https://doi.org/10.3892/etm.2018.6235
Copy and paste a formatted citation
x
Spandidos Publications style
Li W and Jian YB: Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma. Exp Ther Med 16: 529-536, 2018.
APA
Li, W., & Jian, Y. (2018). Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma. Experimental and Therapeutic Medicine, 16, 529-536. https://doi.org/10.3892/etm.2018.6235
MLA
Li, W., Jian, Y."Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma". Experimental and Therapeutic Medicine 16.2 (2018): 529-536.
Chicago
Li, W., Jian, Y."Antitumor necrosis factor‑α antibodies as a novel therapy for hepatocellular carcinoma". Experimental and Therapeutic Medicine 16, no. 2 (2018): 529-536. https://doi.org/10.3892/etm.2018.6235
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team