IL-6, A Promising Tumor Marker and Prognostic Indicator in Patients with HCC

IL-6, A Promising Tumor Marker and Prognostic Indicator in Patients with HCC?

 

Akiyoshi Kinoshita, Hirokazu Nishino

 

Akiyoshi Kinoshita, Hirokazu Nishino, Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, 4-11-1 Izumihon-cho, Komae- shi, Tokyo, 201-8601, Japan

Correspondence to: Akiyoshi Kinoshita, MD, Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, 4-11-1 Izumihon-cho, Komae- shi, Tokyo, 201-8601, Japan.

Email: aki.kino@jikei.ac.jp

Telephone: +81-3-3480-1151           Fax: +81-3-3480-6688

Received: March 27, 2014                Revised: April 19, 2014

Accepted: April 23, 2014

Published online: June 18, 2014

 

ABSTRACT

In the last decade, accumulating evidence has supported Virchow’s hypothesis that cancer and inflammation are linked. Many investigators have demonstrated that the presence of a systemic inflammatory response, as evidenced by an elevated C-reactive protein (CRP) level or elevated interleukin-6 (IL-6) levels, are associated with a poor outcome in patients with many types of cancer, including hepatocellular carcinoma (HCC). In vol 134, issue 1 of the International Journal of Cancer, Ohishi et al have indicated that elevated serum IL-6 levels are associated with an increased HCC risk, independent of other established risk factors for HCC. They found that elevated serum IL-6 levels were associated with an increased risk of HCC, independent of HBV and HCV infection, alcohol consumption, smoking habit, BMI and radiation exposure. In subgroup analyses, they found an even stronger association between elevated serum IL-6 levels and an increased risk of HCC. The authors concluded that monitoring the serum IL-6 levels may be more useful for predicting subsequent HCC, especially among obese individuals with non-B, non-C liver disease.These findings would help clinicians to identify patients with NAFLD or NASH who potentially remain at high risk for the development of HCC.

 

© 2014 ACT. All rights reserved.

 

Key words: Hepatocellular carcinoma; Interleukin-6

 

Kinoshita A, Nishino H. IL-6, A Promising Tumor Marker and Prognostic Indicator in Patients with HCC?. Journal of Tumor 2014; 2(6): 142-144 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/729

 

EDITORIAL

Rudolf Virchow noted a connection between cancer and inflammation in the 19th century, based on the observations that tumors often arose at the sites of chronic inflammation, and that inflammatory cells were present in biopsied tumor tissues. In the last decade, accumulating evidence has supported Virchow’s hypothesis that cancer and inflammation are linked. It is estimated that underlying infections and inflammatory responses are linked to 15-20% of all deaths from cancer worldwide. These include the links between H. pylori and gastric cancer or MALT lymphoma, hepatitis virus and hepatocellular carcinoma (HCC), papillomavirus and cervical cancer and between autoimmune disease or inflammatory bowel disease and colon cancer[1-3]. 

    In the clinical setting, investigators have demonstrated that the presence of a systemic inflammatory response, as evidenced by an elevated C-reactive protein (CRP) level or elevated interleukin-6 (IL-6) levels, are associated with a poor outcome in patients with many types of cancer[4-8].

   With regard to HCC, elevated CRP levels or IL-6 levels were reported to be correlated with a poor prognosis in patients undergoing surgical resection[9,10] or loco-regional therapy[11,12].

    Elevated CRP or IL-6 levels were also demonstrated to be associated with an increased risk of HCC in patients with diffuse type HCC[13], chronic hepatitis B and chronic hepatitis C[14,15]. Giannitrapani et al[16] reported that the serum IL-6 levels were significantly higher in patients with HCC than those in healthy control group. Porta et al[17] showed that IL-6 could be a promising tumor marker for HCC. Moreover, they showed that the diagnostic value of the IL-6 was significantly increased when combined with -fetoprotein (AFP). Recently, Hammad et al[18] indicated that the addition of IL-6, IL-17 and vitamin D to AFP could improve the prognostic ability in patients of HCC.

    More recently, in vol 134, issue 1 of the International Journal of Cancer, Ohishi et al[19] have indicated that elevated serum IL-6 levels are associated with an increased HCC risk, independent of other established risk factors for HCC. They investigated the association between the serum levels of CRP, IL-6 and the risk of HCC using sera collected from a prospective cohort study of atomic bomb survivors. In this nested case-control study, they found that elevated serum IL-6 levels were associated with an increased risk of HCC, independent of HBV and HCV infection, alcohol consumption, smoking habit, BMI and radiation exposure. The association of an elevated serum CRP level with an increased risk of HCC was only marginally significant. Moreover, they performed subgroup analyses to examine the association between IL-6 and the HCC risk in selected subgroups. Among obese subjects (BMI25), an even stronger association was observed between elevated serum IL-6 levels and an increased risk of HCC (all HCC; RR 3.09, non-B, non-C HCC; RR 5.01). Consequently, the authors concluded that monitoring the serum IL-6 levels in combination with established tumor markers, such as AFP or PIVKA-ІІ, may be more useful for predicting subsequent HCC, especially among obese individuals with non-B, non-C liver disease[19].

    IL-6 is a pleiotropic inflammatory cytokine which plays an important role in regulating immune cell growth and differentiation. It is synthesized by many cell types, including T-cells, macrophages and stromal cells, in response to stimulation by tumor necrosis factor- (TNF-) and IL-1[20]. The activation of the IL-6 complex activates Janus kinases (JAK) and signal transducers and activators of transcription (STATs), which regulate cell proliferation and apoptosis[20].

    With regard to HCC, Reichner et al[21] demonstrated that the overexpression of IL-6 increased metastatic potential of rat HCC cells. Sakurai et al[22] showed that the release of IL-1a by necrotic hepatocytes promotes the production of IL-6, stimulates compensatory proliferation and increases hepatocarcinogenesis in the diethylnitrosamine mouse model. Meanwhile, Park et al[23] demonstrated that the development of obesity-promoted HCC is dependent on the enhanced production of IL-6 and TNF via the activation of signal transducer and activator of transcription 3 (STAT3) in the diethylnitrosamine mouse model. Inhibition of STAT3 activity with several agents in HCC cells was showed to lead to the induction of apoptosis, reduction in colony-forming ability and enhanced chemosensitivity in HCC cells[24-26]. These experimental studies support the findings by Ohishi et al.

    The study by Ohishi et al indicates the role of IL-6 as a promising tumor marker for HCC, especially among obese subjects with non-B, non-C liver disease, such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

    In conclusion, these findings would help clinicians to identify patients with NAFLD or NASH who potentially remain at high risk for the development of HCC.

 

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

 

REFERENCES

1     Balkwill F, Mantovani A. Inflammation and cancer: back to Vichow? Lancet 2001, 357: 539-545

2     Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008, 454: 436-444

3      Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 2013; 13: 759-771

4      Heikkila K, Ebrahim S, Lawlor DA. A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health 2007; 61: 824-833

5     Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol 2010; 6: 149-163

6     Ko YJ, Kwon YM, Kim KH, Choi HC, Chun SH, Yoon HJ, Goh E, Cho B, Park M. High-sensitivity C-reactive protein levels and cancer mortality. Cancer Epidemiol Biomarkers Prev 2012; 21: 2076-2086

7      Michalaki V, Syrigos K, Charles P, Waxman J. Serum levels of IL-6 and TNF-alpha correlate with clinicopathological features and patient survival in patients with prostate cancer. Br J Cancer 2004; 90: 2312-2316

8       Andrews B, Shariat SF, Kim JH, Wheeler TM, Slawin KM, Lerner SP. Preoperative plasma levels of interleukin-6 and its soluble receptor predict disease recurrence and survival of patients with bladder cancer. J Urol 2002; 167: 1475-1481

9      Hashimoto K, Ikeda Y, Korenaga D, Tanoue K, Hamatake M, Kawasaki K, Yamaoka T, Iwatani Y, Akazawa K, Takenaka K. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer 2005; 103: 1856-1864

10    Pang XH, Zhang JP, Zhang YJ, Yan J, Pei XQ, Zhang YQ, Li JQ, Zheng L, Chen MS. Preoperative levels of serum interleukin-6 in patients with hepatocellular carcinoma. Hepatogastroenterology. 2011; 58: 1687-1693

11    Kinoshita A, Onoda H, Takano K, Imai N, Saeki C, Fushiya N, Miyakawa Y, Nishino H, Tajiri. Pretreatment serum C-reactive protein level predicts poor prognosis in patients with hepatocellular carcinoma. Med Oncol 2012; 29: 2800-2808

12    Sieghart W, Pinter M, Hucke F, Graziadei I, Schöniger-Hekele M, Müller C, Vogel W, Trauner M, Peck-Radosavljevic M. Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma. Hepatology 2013; 57: 2224-2234

13    Lin ZY, Wang LY, Yu ML, Chen SC, Chuang WL, Hsieh MY, Tsai JF, Chang WY. Role of serum C-reactive protein as a marker of hepatocellular carcinoma in patients with cirrhosis. J Gastroenterol Hepatol 2000; 15: 417-421

14     Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, Ng EK, Chan FK, Sung JJ, Chan HL. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatiis B. Int J Cancer 2009; 124: 2766-2770

15    Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M. Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 2009; 125: 2264-2269

16     Giannitrapani L, Cervello M, Soresi M, Notarbartolo M, La Rosa M, Virruso L, D’Alessandro N, Montalto G. Circulating IL-6 and sIL-6R in patients with hepatocellular carcinoma. Ann N Y Acad Sci 2002; 963: 46-52

17     Porta C, De Amici M, Quaglini S, Paglino C, Tagliani F, Boncimino A, Moratti R, Corazza GR. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol 2008; 19: 353-358

18    Hammad LN, Abdelraouf SM, Hassanein FS, Mohamed WA, Schaalan MF: Circulating IL-6, IL-17 and vitamin D in hepatocellular carcinoma: potential biomarkers for a more favorable prognosis?  J Immunotoxicol 2013; 10: 380-386

19    Ohishi W, Cologne JB, Fujiwara S, Suzuki G, Hayashi T, Niwa Y, Akahoshi M, Ueda K, Tsuge M, Chayama K. Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer 2014; 134: 154-163

20     Heikkilä K1, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer. 2008; 44: 937-945

21   Reichner JS, Mulligan JA, Spisni R, Sotomayor EA, Albina JE, Bland KI. Effect of IL-6 overexpression on the metastatic potential of rat hepatocellular carcinoma cells. Ann Surg Oncol 1998; 5: 279-286

22    Sakurai T1, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, Karin M. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 2008; 14: 156-165

23    Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140: 197-208

24    Lau CK, Yang ZF, Lam SP, Lam CT, Ngai P, Tam KH, Poon RT, Fan ST. Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma. Cancer Biol Ther 2007; 6: 1900-1907

25    Liu Y, Li PK, Li C, Lin J. Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem 2010; 285: 27429-27439

26    Beyazit Y, Kekilli M, Kurt M, Sayilir A, Tas A, Onal IK. Role of IL-6 activated STAT3 and TNF expression in obesity-associated hepatocellular carcinoma. Aliment Pharmacol Ther 2010; 32: 304-305

 

Peer reviewer: Hua Yang, Ph.D, Department of Cell Biology, Peking University, Xueyuan Road 38, Haidian District, Beijing, 100191, China.

 

 

 

 

 

 

 

 

 

 

 

 

 

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