In the recently published paper by Xie et al1 in the journal of Drug Design, Development
and Therapy, the authors have evaluated interleukin (IL)-17–driven inflammatory responses
in 17 cases of human colon adenocarcinomas, 16 cases of human normal colon tissues
adjacent to the resected colon adenocarcinomas, ten cases of human ulcerative colitis
tissues from biopsies, and eight cases of human benign colon polyps. The authors have
observed that human colon adenocarcinomas contained the highest levels of IL-17, which
was significantly higher than the IL-17 level in the adenomas, ulcerative colitis,
and normal colon tissues (P<0.01). The levels of IL-17 receptor A (IL-17RA) were also
the highest in human colon adenocarcinomas, followed by adenomas and ulcerative colitis.
The increased level of IL-17 and IL-17RA was accompanied with increased IL-17–driven
inflammatory responses, including activation of extracellular signal-regulated kinase
1/2 and c-Jun N-terminal kinase pathways, increased expression of matrix metalloproteinase
(MMP)-9, MMP-7, MMP-2, B-cell lymphoma, and cyclin D1, decreased expression of Bcl-2-associated
X protein, and increased expression of vascular endothelial growth factor (VEGF) and
VEGF receptor expression that were associated with increased angiogenesis.1 These
data suggest that IL-17–driven inflammatory responses contribute to the initiation,
growth, development, and metastasis of colon cancer. IL-17 and its related signaling
pathways may serve as promising novel targets in the development of drugs for the
prevention and treatment of colon cancer.
The relationship between IL-17 and tumor growth was first reported in 1999 by Tartour
et al2 who showed that IL-17 served as a tumor growth factor in nude mice, although
its mechanism remained unclear. Currently, six IL-17 family members have been identified,
including IL-17A (namely IL-17), IL-17B (also named IL-20), IL-17C, IL-17D (also named
IL-27), IL-17E (also named IL-25), and IL-17F.3 IL-17A binds the receptor complex
IL-17RA–IL-17RC to drive inflammatory gene expression. IL-17 is a cytokine produced
by Th17 cells, a T helper cell subset developed from an activated CD4+ T cell that
is characterized by the expression of intracellular retinoic acid-receptor–related
orphan receptor γt and signal transducer and activator of transcription 3 (STAT3).
Th17 cells secrete IL-17A, IL-17F, IL-21, and IL-22 to fight extracellular bacteria
and fungi by stimulating epithelial cells to produce chemokines and cytokines, which
drive the immune response. Other cells, including γδT cells, natural killer (NK) cells,
NK T cells, mast cells, and granulocytes can also secrete IL-17. Phosphorylation of
STAT3, the downstream signal of IL-6 and IL-21, is a key process in the differentiation
of Th17 cells in the presence of transforming growth factor (TGF)-β1.4
IL-17 plays an important role in inflammation, immunity, and autoimmunity and has
been associated with many immune-related/autoimmune diseases, including rheumatoid
arthritis, multiple sclerosis, psoriasis, lupus, asthma, allograft rejection, autoimmune
hepatitis, and inflammatory bowel disease.5–7 IL-17 has proinflammatory effects on
a panel of cellular targets, such as epithelium, endothelium, and monocytes/macrophages.
IL-17 can stimulate the production of a variety of cytokines such as IL-1β, IL-6,
tumor necrosis factor (TNF)-α, and TGF-β, chemokines such as IL-8, and prostaglandins
from macrophages, endothelial cells, epithelial cells, and fibroblasts, resulting
in and amplifying inflammation.4,6,8–11 IL-17–triggered release of IL-6 will consequently
activate the STAT3 pathway, which will further activate the nuclear factor (NF)-κB
pathway.3,5 IL-6 promotes the differentiation of Th17 cells, and IL-17 amplifies IL-6
production in the tumor.
STAT3 is a critical signaling molecule that is involved in the formation of the tumor
microenvironment through regulating downstream proinflammatory cytokines and factors
promoting tumor growth, progression, and metastasis.8,12–15 Constitutively active
phosphorylated STAT3 can regulate the differentiation and maturation of Th17 cells
to secrete IL-17, which in turn positively feeds back to STAT3 signaling and induces
more IL-17 production.8,12–14 IL-17 promotes the recruitment and infiltration of myeloid-derived
suppressor cells (MDSCs), such as CD11b+Gr1+ cells, to the tumor environment; IL-17
also augments the development and function of MDSCs.4 Furthermore, IL-17 produced
by MDSCs recruits T regulatory cells at tumor sites via upregulation of chemokines
CCL17 and CCL22 and enhances their suppressor function via upregulation of CD39 and
CD73.4 MDSCs produce nitric oxide and reactive oxygen species (ROS) and suppress T-cell
function through modification of T-cell receptors, inhibition of Janus kinase 3 and
STAT5, inhibition of major histocompatibility complex class II expression, and induction
of T-cell apoptosis.16,17 Meanwhile, IL-17 can enhance the growth of vascular endothelial
cells and influence the angiogenic progress by increasing the secretion of cytokines,
such as TNF-α, IL-8, and VEGF.4 IL-17 promotes the invasion of cancer cells via upregulating
the expression of MMP-2 and MMP-9 and downregulating the expression of tissue inhibitor
of MMP-1 and MMP-2.4 The increased expression of chemokines by IL-17 attracts neutrophils
but not eosinophils.
IL-17 plays a dual role in serving either as a promoter or antitumor factor depending
on the type of tumors and the existence of host immune system. In mice, IL-17 promotes
an antitumor cytotoxic T-cell and NK-cell response, leading to tumor regression of
fibrosarcoma, hematopoietic immunogenic tumor, and lung melanoma; IL-17A has showed
a protective effect against chronic lymphocytic leukemia development by promoting
immune system-mediated tumor rejection.4,6,9,10 Adaptive transfer of Th17 cells reduced
tumor growth because Th17 cells developed into Th1 cells in vivo and produced interferon
(IFN)-γ and promoted the activation of cytotoxic T lymphocytes.4,6,9,10 On the other
hand, IL-17 promotes tumorigenesis, proliferation, angiogenesis, and metastasis of
many types of tumors.4,6,9,10 IL-17−/− mice have been used to determine the endogenous
IL-17A functions with regard to tumor progression. One study using B16 melanoma cell
lines has showed that IL-17A promoted tumor growth via angiogenesis and induced IL-6
production, which in turn activated oncogenic STAT3, upregulating prosurvival and
proangiogenic genes.14 However, another study using MC38 colon cancer cell lines has
showed that IL-17A inhibited tumor growth through antitumor immunity.18 IL-17 has
been detected in various tumors, including breast cancer, gastric cancer, colorectal
cancer, cervical cancer, brain tumor, intrahepatic cholangiocarcinoma, and hepatocellular
carcinoma.4 The sources of Th17 cells in cancer may include the trafficking of circulating
Th17 cells to tumors and locally induced Th17 cells. The recruitment of Th17 cells
is mainly mediated by CCR2-CCL2, CCR4-CCL17/CCL22, and CCR6-CCL20 pathways.4–7 The
Th1 cytokines, such as IFN-γ, and Th2 cytokines, such as IL-4, regulate the differentiation
and development of Th17 cells.4,6,9,10 The number of Th17 cells gradually increases
in the tumor microenvironment during tumor development, and this increase is positively
associated with poor prognosis in patients with cancer.4
In the 19th century, Dr Rudolf Virchow observed the infiltration of leukocytes in
tumor tissues, offering the first indication of a potential link between cancer and
inflammation. Up to date, there is enough evidence that inflammation plays a critical
role in tumor initiation, growth, and development.19–23 A key role for inflammation
in carcinogenesis is generally accepted by cancer scientists, and it has become evident
that an inflammatory microenvironment is an essential component of all types of tumor.
It is known that only a minority of cancers (<10%) are caused by germline mutations,
while the vast majority (90%) are ascribed to somatic mutations and environmental
factors.20,22–26 Many cancers are associated with certain forms of chronic inflammation
and 15%−20% of cancers are linked to chronic infections.20,22–26
It is now well established that the induction of inflammation by bacterial and viral
infections increases cancer risk. Chronic Helicobacter pylori infection is associated
with gastric cancer and mucosa-associated lymphoid tissue lymphoma; Chlamydia trachomatis
infection increases the risk of cervical cancer;27 enterotoxigenic Bacteroides fragilis
infection promotes colon tumorigenesis.28 Viral infections by high-risk human papillomavirus
(HPV) subtypes, such as HPV16 and HPV18, are causal to the development of cervical,
anal, and genital cancers.29,30 Infections with hepatitis B or C viruses increase
the risk of hepatocellular carcinoma;31 the Epstein–Barr virus can cause lymphomas
and nasopharyngeal cancer;32 human herpes virus 8 (also known as Kaposi sarcoma-associated
herpes virus) causes Kaposi sarcoma;33 HIV infection has been linked to a higher risk
of developing Kaposi sarcoma and cervical cancer;34 human T-lymphotrophic virus-1
has been linked with adult T-cell leukemia/lymphoma;35 Merkel cell polyomavirus causes
Merkel cell carcinoma.36 Schistosomiasis is associated with the development of bladder
cancer;37
Opisthorchis viverrini and Clonorchis sinensis infection are linked to increased risk
of cholangiocarcinoma.38 Microorganisms may manipulate and/or collaborate with cellular
signaling pathways to promote an inflammatory microenvironment that facilitates cancer
development.
Another type of chronic inflammation that precedes tumor development is caused by
immune deregulation and autoimmunity.20,22–26 A typical example is inflammatory bowel
disease, which significantly increases the risk of colorectal cancer. Chronic inflammation
associated with infections or autoimmune disease precedes carcinogenesis and can contribute
to it through induction of oncogenic mutations and activation of oncogenes, inactivation
of tumor suppressors, genomic instability, early tumor promotion, and enhanced angiogenesis.20,22–26
Prolonged exposure to environmental irritants (eg, smoking or asbestos) or obesity
can also result in low-grade chronic inflammation that precedes tumor development.
Particulate materials from tobacco smoke and other environmental irritants can precipitate
chronic obstructive pulmonary disease, a condition associated with higher lung cancer
risk.39,40 The precise mechanisms that underlie the association of obesity with increased
risk for tumors, including mammary, renal, esophageal, gastrointestinal and reproductive
cancers, remain elusive. The obese setting provides a unique adipose tissue microenvironment
with concomitant systemic endocrine alterations favoring both tumor initiation and
progression, and considerable metabolic differences are induced by tumor cells in
the stromal vascular fraction that surrounds them.41
The inflammatory response can promote angiogenesis, oncogene mutation, tumor progression
and metastasis, immunosuppression, and genomic instability. Cancer therapy can also
trigger an inflammatory response by causing trauma, necrosis, and tissue injury that
stimulate tumor reemergence and resistance to therapy.19 Most solid tumors trigger
an intrinsic inflammatory response that builds up a protumorigenic microenvironment.
Other tumors, for instance lung cancer, can promote inflammation through active secretion
of proinflammatory molecules, such as the extracellular matrix component versican,
which activates macrophages through Toll-like receptor 2.21,23
The tumor microenvironment is a complex ecology of cells that evolves with and provides
support to tumor cells during the transition to malignancy, which facilitates inflammation
initiation, development, and amplification.22,42,43 As a result of different forms
of inflammation, the tumor microenvironment contains innate immune cells, including
macrophages, neutrophils, mast cells, MDSCs, dendritic cells, and NK cells and adaptive
immune cells (T and B lymphocytes) in addition to the cancer cells and their surrounding
stroma consisting of fibroblasts, endothelial cells, pericytes, and mesenchymal cells.20,22,44
These different types of functional cells communicate with each other by means of
direct contact or cytokine and chemokine production and act in autocrine and paracrine
manners to shape the tumor environment. The expression of various immune mediators
and modulators as well as the abundance and activation state of different cell types
in the tumor microenvironment dictate in which direction the balance is tipped and
whether tumor-promoting inflammation or antitumor immunity will ensue.42,43 In established
tumors, this balance is profoundly tilted toward protumor inflammation, since the
tumor rarely regresses spontaneously without therapeutic intervention.
The primary immune cells found within the tumor microenvironment are tumor-associated
macrophages (TAMs) and T lymphocytes.21,23,42,43 TAMs promote many important features
of tumor progression, including angiogenesis, tumor cell invasion, motility, and intravasation
as well as at the metastatic site, stimulation of tumor cell extravasation, and persistent
growth.45,46 TAMs express an array of effector molecules that inhibit the antitumor
immune responses; this includes cell surface receptors, cytokines, chemokines, and
enzymes that can suppress CD4+ and CD8+ T-cell effector function directly or indirectly
by recruitment of natural regulatory T cells to the tumor microenvironment, as well
as by inducing the CD4+ regulatory fraction cells and sustaining their survival.46
TAMs can also suppress T-cell activity by the depletion of L-arginine in the tumor
microenvironment. They also modulate therapeutic response and induce multidrug resistance.47
Mature T cells are divided into two major groups based on the T-cell receptors they
produce: αβ and γδ. αβT cells are further classified into CD8+ cytotoxic T cells and
CD4+ Th cells, including Th1, Th2, Th17, and T regulatory cells, as well as NK T cells
with four different groups.22,42,43,48 Similar to TAMs, the tumor-promoting activity
of T cells are mediated by cytokines, whereas both cytokines and cytotoxic mechanisms
mediate the antitumorigenic function of T lymphocytes. TAMs and T cells in tumors
may represent useful therapeutic targets for the development of new interventions.
The cytokines and chemokines produced by various effector cells in the tumor microenvironment
play a critical role in tumor initiation and development.22,43 Different cytokines
can either promote or inhibit tumor development, growth, and metastasis. Several cytokines,
such as macrophage migratory inhibitory factor, TNF-α, IL-4, IL-6, IL-10, IL-12, IL-17,
IL-23, and TGF-β, have been shown to either promote or inhibit tumor development.22,43
Malignant cells or inflammatory cells in the tumor microenvironment can produce TNF-α,
and TNF-α signaling can promote cell survival, angiogenesis, progression, and metastasis.
Other effects of TNF-α include impairment of immune surveillance through T-cell suppression
and inhibition of the cytotoxic activity of activated macrophages. IL-6, a pleiotropic
inflammatory cytokine, is considered a key growth factor for both malignant and immune
cells.49,50 IL-6 acts intrinsically on tumor cells through numerous downstream mediators
to support cancer cell proliferation, survival, and metastatic dissemination. IL-6
can also act extrinsically on other cells within the complex tumor microenvironment
to sustain a protumor milieu by supporting angiogenesis and tumor evasion of immune
surveillance.49,50 IL-10 is an immunosuppressive and anti-inflammatory cytokine that
is also linked with inflammation-associated cancer. IL-12 is a cytokine that promotes
cell-mediated immunity by promoting Th1-type cytokine responses, enhancing the lytic
activity of NK/lymphokine-activated killer cells, augmenting specific cytotoxic T-lymphocyte
responses, and inducing the production of IFN-γ while it suppresses the development
of Th2-type cytokine responses and humoral immunity.51 IL-23 can activate STAT4 through
IL-23 receptors distributed on the membrane of T cells, NK cells, monocytes, and dendritic
cells; it is involved in the inflammatory response through promoting MMP-9, enhancing
angiogenesis and suppressing CD8+ T-cell infiltration; IL-23 can induce and promote
the differentiation of CD4+-naïve T cells to Th17 cells that produce IL-17A, IL-17F,
IL-21, and IL-22.51 TGF-β can inhibit epithelial cell cycle progression and promote
apoptosis, contributing to tumor initiation and progression inhibition, but TGF-β
also promotes epithelial-to-mesenchymal transition that has been associated with increased
tumor cell motility, invasion, and metastasis.52,53 Various cytokines can activate
downstream effectors such as NF-κB, STAT3/4, and SMADs, therefore controlling the
immune and inflammatory milieu to either favor antitumor immunity or enhance tumor
progression.12,22,42
The biochemical mechanisms of how inflammation initiates and promotes tumor development
is not fully understood. An inflammatory microenvironment can augment mutation rates
and the proliferation of mutated cells. Activated inflammatory cells generate mutagenic
ROS, reactive nitrogen intermediates, and other products that can induce marked DNA
damage and genomic instability.22,24,25 Inflammatory cells may utilize proinflammatory
cytokines such as TNF-α to stimulate ROS accumulation in neighboring epithelial cells.
Cytokines offer malignant cells a continuous supply of growth and survival signals
in an initially hostile microenvironment.42,43 A panel of growth factors and cytokines
produced in the tumor microenvironment can confer a stem cell-like phenotype upon
tumor progenitors or stimulate stem cell expansion, thereby enlarging the cell pool
that is targeted by environmental mutagens. An inflammatory environment also promotes
epithelial-to-mesenchymal transition. In most cases, cancer-promoting cytokines act
in a paracrine manner, while some cancer cells produce their own cytokines (eg, IL-6).42,43
To date, there is enough evidence indicating that inflammation can influence every
step of tumor initiation, development, and progression as well as the response to
therapeutic intervention. In the past decade, we have learned a great deal about the
complicated mechanisms by which cancer and inflammation interplay, and clearly we
should consider inflammation as a new therapeutic target in cancer treatment. Modulation
of inflammation may be also a useful approach to reduce cancer risk. Prevention is
a much better and more economical way to fight cancer than treating an advanced disease.
More studies are warranted to explore how inflammation induces and promotes tumorigenesis
and if anti-inflammatory therapies should be integrated into current cancer treatment
regimens.
Because IL-17 plays an important role in the initiation and development of cancer,
it represents an interesting target in cancer treatment. Anti–IL-17 monoclonal antibodies
have been tested for the treatment of inflammatory autoimmune conditions, including
rheumatoid arthritis, psoriasis, and inflammatory bowel disease.54,55 In January 2015,
the US Food and Drug Administration approved the use of secukinumab (trade name Cosentyx™),
an IL-17 inhibiting monoclonal antibody, for the treatment of moderate-to-severe plaque
psoriasis. Ixekizumab (anti–IL-17 monoclonal antibody) and brodalumab (IL-17RA monoclonal
antibody) has been shown to be effective in the treatment of patients with moderate-to-severe
plaque psoriasis. The anti–IL-12- and IL-23 antibody ustekinumab can also be used
to effectively treat psoriasis by reducing IL-17.56 There is preliminary evidence
from animal studies that inhibition of IL-17 can induce tumor regression.4,57 Further
studies are certainly needed to explore the role of IL-17 in tumor biology, pathology,
diagnosis, and treatment.