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 (BMI≥25), 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.
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Peer reviewer: Hua Yang, Ph.D,
Department of Cell Biology, Peking University, Xueyuan Road 38, Haidian
District, Beijing, 100191, China.
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