Interleukin-6 Cytokine: A Multifunctional Glycoprotein for Cancer
www.omicsonline.com/open-access/1745-7580/1745-7580-9-062.pdf
Abstract
Interleukin 6 is a multifunctional cytokine. Its increased levels have been associated with elevated cancer risk,
and also these levels have been found to be a prognostic factor for several cancer types. In addition, increased
levels have been found in coronary heart disease, insulin resistant patients, advance stage cancer patients, atopy/
asthma and in patients with blood circulating micrometastasis. Additionally several studies with different types of
cancers have been performed to identify the correlation between interleukin-6 levels, stage, treatment response and
severity of symptoms. The influence of interleukin-6 is performed mainly through the janus kinase-signal transducer
and activator of transcription-zinc finger protein 1-2 signaling pathway. As a result, the increased levels of interleukin-6
are responsible for enhanced neo-angiogenesis, inhibition of cancer cell apoptosis and deregulation of the control
mechanisms in the microenvironment. In addition, increased levels of inteleukin-6 have been found to increase the
production of collagen and a-actin which induce interstitial lung disease. In the current mini review we will present
information regarding the interleukin-6 and published results in several cancer studies and finally we will comment in
future treatment approaches blocking this cytokine in cancer patients.
Introduction
Interleukin-6 (IL-6) is a multifunctional cytokine that influences
the activity of cancer cells. It is a glycoprotein which consists of 184
amino acids and has 26 kilodaltons (kDa) as a molecular weight [1]. It
is involved in tumor growth, malignant differentiation of cancer cells
and microenvironment immunomodulation [2]. These properties are a
result of enhanced neo-angiogenesis, inhibition of cancer cell apoptosis
and acquired cell resistance [3]. Again these results are mediated through
several signaling pathways, however; the most important ones are the
transcription activator 3 and the signal transducer [4-9]. Interleukin-6
levels have been observed elevated in advanced stage cancer [10]
and again elevated levels have been associated with increased risk of
cancer [11,12]. Moreover; IL-6 has been found to be a cancer disease
prognostic marker [13] and also it was increased in patients with cancer
induced cachexia [14]. Interleukin-6 has been found overexpressed in
cancer cells lines expressing epidermal growth factor receptor (EGFR)
mutation [4], however; in another study further investigation of the
levels of IL-6 after tyrosine kinase inhibitors (TKIs) indicated that
TKIs induce apoptosis, but at the same time increase IL-6 levels [15].
During the cancer, cell apoptosis growth factors, which stimulate the
IL-6 release, circulate in the extracellular matrix. The increased levels
of interleukin-6 subsequently induced collagen and a-actin production
and interstitial lung disease pattern was observed. In addition, there are
few data whether IL-6 levels are associated with treatment effectiveness
or cancer stage for patients with EGFR mutations [10]. IL-6 receptor
mutation has been investigated in mice and it was observed that the
animals carrying this mutation had additionally overexpression of
signal transducer and activator of transcription 3 (STAT3) activities. In
these animals the extent of the infiltrates was directly associated with
the overexpression of the stat-3 signaling pathway [16]. Furthermore;
increased levels of IL-6 have been associated with increased lung cancer
risk in lifetime non-smoking women with asthma/atopy [17]. Increased
levels of IL-6 have been found in patients with coronary heart disease
[18] and insulin resistance has been reported from increased levels of
IL-6 in a lung cancer patient [19]. Several trials have been performed
investigating the IL-6 levels and the effects on the prognosis, stage,
treatment outcome and cancer relapse. Regarding surgically resected
patients the higher the interleukin-6 levels after the first day, the sooner
was the relapse [20]. These studies can be summarized according to
each cancer type as follows: a) ocular [21], b) lung EGFR mutation
positive adenocarcinomas [4,15], c) colorectal [22], d) small cell lung
cancer [3], e) brain [2,23], f) cancer stem cells [24,9], g) head and neck
[25], h) hepatocellular [26], i) breast [27], j) melanoma [28], k) bone
[29] and l) nasopharyngeal cancer cells [30].
Search Methods
We performed an electronic article search through PubMed,
Google Scholar, Medscape, and Scopus databases, using combinations
of the following keywords: interleukin-6, cancer, angiogenesis, and
cytokine. All types of articles (randomized controlled trials, clinical
observational cohort studies, review articles, case reports) were
included. Selected references from identified articles were searched for
further consideration, without language limitation.
IL-6 targeted treatment
Targeting the signaling pathway of the IL-6 is a novel target. The
tissue inhibitor of metalloproteinase-3 (TIMP-3) is a possible target.
It has been previously observed that low TIMP-3 and high IL-6
levels patients had lower survival [33]. The novel (2E,5E)-2,5-bis(4-
(3(dimethylamino)-propoxy) benzylidene) cyclopentanone (A13) has
been observed to reduce nitric oxide (NO), TNF-a, HGF and IL-6. In
addition, it reduces damages to the lung and reduced pain in several
induced inflammatory models [34]. Neutralizing IL-6 antibodies have
been used to block the JAK1-STAT3 signaling pathway in a lung cancer
model [5]. Tocilizumab an anti-IL-6R antibody has been used and
apart from reducing the lung cancer tumorigenic activities it was also
observed to reduce the cancer related cachexia [14]. Toll like receptor 2
is a novel molecule under consideration as a future immunomodulatory
therapy for targeting tumor inflammation. Previous positive results
have been published in a melanoma model [35]. Moreover, another
novel IL-6R blocker which is under investigation is siltuximab [36].
This novel agent has been used also in combination with docetaxel
chemotherapy [37]. The IL-6R antibodies will be soon replaced by
nonantibody-based inhibitors called avimers. Their main advantage
is that they do not induce allergic reactions and have more prolonged
activity in comparison to the antibodies (> two weeks). Currently the
AMG-220 is being developed by AVIDA [38].
Discussion
Inflammation cytokines such as: a) C-reactive protein, b) IL-6 and
IL-8have been identified as lung cancer markers. Increased plasma
levels of these cytokines have been associated with increased for risk
lung cancer [39,12,11]. However, only IL-8 has been identified as
an early lung cancer biomarker (more than 2 years whereas IL-6 for
<2 years) [11]. Also in never smokers, different polymorphisms of
inflammatory pathway genes are also related with increased lung cancer
risk, especially IL-6, IL-1ß and IL-1RN [40]. Increased levels of IL-6
have been observed in advanced stage cancer in several cancer types
[41]. Caregivers of cancer patients with advanced stage lung cancer
have also high levels of IL-6 and other inflammatory markers, which
are reduced when the cancer patient is treated efficiently [41]. A joint
effect of asthma/atopy and IL-6 gene polymorphism in lung cancer
has been identified in lifetime non-smoking Chinese women [17]. The
IL-6 levels have been also associated with coronary heart disease and
efforts have been made to target the IL-6 receptor as a treatment for
coronary heart disease [18]. Moreover, IL-6 levels have been identified
as a marker for EMT malignant transition in lymph nodes [25]. Insulin
allergy and immunologic insulin resistance has been identified in a
patient with lung cancer in the pre-chemotherapy period. In specific
due to excessive IL-6 plasma levels >96.4 pg/ml (reference range <4 pg/
ml) local skin irritation (erythema) was observed in the site of insulin
administration and the HbA1c levels were deregulated. In addition,
increased IgG anti-insulin antibodies were observed. All the excessive
laboratory parameters return to normal after chemotherapy initiation [19].
Moreover, different pro-inflammatory and fibrogenic cytokines
have been investigated in correlation to radiation induced lung toxicity
(RILT) and it was observed that low pretreatment levels of IL-8 were
correlated with the development of RILT. In addition, if IL-8 and
TGF-ß1 levels were combined, then an independent prognostic cluster
was formed for RILT development [42]. Increased levels of IL-6,
collagen and a-actin have been found after TKI inhibitor treatment in
lung cancer cell lines and tongue cancer HSC-3 cells. The treatment
efficiency was associated with the fibrogenic activity [15]. Again in
the study by O`Donoghue in interstitial fibrosis patients elevated
levels of IL-6 were correlated with overexpression of STAT3 signaling
pathway and enhanced fibrogenic activity. Therefore, fibrotic lesions are
expected when IL-6 levels are elevated; however, no clear association
has been made between the levels and extent of the lesions. There is
however literature for stage IIIB and IV lung cancer patients regarding
their treatment response and IL-6 serum levels. It has been observed
that increased levels of circulating IL-6 are a prognostic factor for poor
treatment response [10]. The raltitrexed, which is a specific thymidylate
synthase inhibitor when administered in colorectal cancer patients
with or without chemotherapy activated a cascade of cytokines and
chemokines and the identification of infection in these patients was
impossible. Again, we would like to have data regarding the fibrogenic
activation in these patients with radiologic findings [22]. Neutralizing
IL-6 antibodies are on the market and they have been observed to
reduce cancer related cachexia [14]. However, we would like to have a
study with sleep disturbances and IL-6R antibody treatment. Regarding
the factors that are mediated by IL-6 in several cancer types, we can
summarize them to the following. a) Multiple myeloma (MyC regulator
gene, STAT3, fibroblast growth factor (FGFR))[43], b) lung cancer
(EGFR, STAT3) [4], c) colon cancer (STAT3, c-Myc) [44], d) prostate
cancer (IGF-1R, Human Epidermal Growth Factor Receptor 2 (Erb2))
[45], e) breast cancer (Notch, Rat sarcoma (Ras), Human Epidermal
Growth Factor Receptor 2 (HER2)) [46], f) ovarian cancer (Stat3,
VEGF) [47] and g) bladder cancer nuclear factor kappa-light-chainenhancer
of activated B cells (Nf-kappaB) [48].
Finally, the immune system has a dual role, it can either enhance
the tumor growth and tumor metastasis, however, it can also protect
the body from carcinogenesis and metastasis [49]. Therefore, a balance
is necessary since not all cytokines are responsible for enhancing the
tumor microenvironment and tumor activities.
