Deregulated inflammatory response plays a pivotal role in the initiation, development and progression of tumours. Potential molecular mechanism(s) that drive the establishment of an inflammatory-tumour microenvironment is not entirely understood owing to the complex cross-talk between pro-inflammatory and tumorigenic mediators such as cytokines, chemokines, oncogenes, enzymes, transcription factors and immune cells. These molecular mediators are critical linchpins between inflammation and cancer, and their activation and/or deactivation are influenced by both extrinsic (i.e. environmental and lifestyle) and intrinsic (i.e. hereditary) factors. At present, the research pertaining to inflammation-associated cancers is accumulating at an exponential rate. Interest stems from hope that new therapeutic strategies against molecular mediators can be identified to assist in cancer treatment and patient management. The present review outlines the various molecular and cellular inflammatory mediators responsible for tumour initiation, progression and development, and discusses the critical role of chronic inflammation in tumorigenesis.

INTRODUCTION

Cancer is characterized by uncontrolled proliferation of cells, often resulting in invasion and metastasis to both nearby and distant tissues and organs. Besides cardiovascular diseases, cancer is one of the leading causes of death worldwide despite medical advancements through the years. As early as 150 years ago, Rudolf Virchow noted the presence of leucocytes within tumour tissues, suggesting that cancer may develop from chronic inflammation [1,2]. However, only after numerous laboratory and population-based studies, has Virchow's observation that cancer arose from prolonged inflammation been verified. Yet, to date, studies are still ongoing to detail the intricate link between inflammation and cancer.

Inflammation is the body's natural defence mechanism against microbial infection and other noxious stimuli, which inevitably cause tissue damage. By recruiting inflammatory cells to the site of damage, a host of inflammatory mediators is secreted with the goal of promoting tissue breakdown and strengthening host defence against potential infections by various pathogens [3,4]. Acute inflammation contributes to cancer regression [4,5], whereas chronic inflammation promotes cancer progression [6]. Upon tissue damage, pre-stationed mast cells and macrophages secrete molecules that regulate the migration of leucocytes and inflammatory cells to the site of damage. The migration of leucocytes and inflammatory cells primarily serves to promote tissue breakdown as well as strengthening the defence against potential infection from microbes [3] and damage from noxious stimuli [2]. Inflammatory processes in general involve an intricate and complex cross-talk between a host of inflammatory mediators and enzymatic pathways [4]. Despite the observed trend that chronic inflammation increases tumorigenic tendency, the benefits of inflammation should not be discounted. Activation of the inflammatory response is initiated when components of micro-organisms bind to TLRs (Toll-like receptors). TLRs are pattern-recognition receptors that may serve either pro- or anti-tumorigenic purposes; TLR4 has been demonstrated to promote intestinal tumorigenesis, whereas TLR2 protects against colitis-associated cancer [7]. This dual-functionality of TLRs demonstrates the versatility of inflammatory responses, where an inflammatory mediator may contribute either to tumorigenesis or serve as a potential therapeutic option.

Often, acute inflammation is followed by rapid resolution where irritants are cleared from the host. However, when resolution fails, a state of chronic inflammation ensues owing to excess production of cytokines, chemokines and growth factors that inevitably lead to uncontrolled inflammatory reactions [2]. Since Virchow's observation, numerous studies have been conducted and the results obtained support his hypothesis that cancer can result from chronic inflammation. To date, approximately 20% of cancer deaths are associated with chronic infection and inflammation [8]. To deter inflammation-associated tumorigenesis, it is essential to maintain a balance in the production of pro-inflammatory and anti-inflammatory mediators. Although a tumorigenic trend is observed from the transformation of acute to chronic inflammatory state, caution must be practised before exerting a claim that all inflammatory processes may always elicit pathogenic consequences.

By inducing DNA damage and chromosomal instability, chemokines, cytokines and growth factors produced at sites of chronic inflammation can predispose to and potentially initiate cancer in the host [2]. At present, details regarding the pathogenesis of cancer arising from inflammation are accumulating at an exponential rate. There are two different paradigms to the link between inflammation and cancer: (i) the intrinsic pathway, and (ii) the extrinsic pathway [9]. DNA damage, chromosomal instability and epigenetic alterations that consequently lead to inappropriate gene expression exemplify the intrinsic pathway, whereas inflammatory signals from infections and autoimmune diseases are associated with the extrinsic pathway. Both pathways activate various important transcription factors [including NF-κB (nuclear factor κB) and STAT3 (signal transducer and activator of transcription 3)] that are key inducers of the inflammatory cascade [10,11]. It is of no surprise that activation of these pro-inflammatory cascades leads to (i) enhancement of cell proliferation, (ii) apoptotic evasion, (iii) invasion and metastasis, and (iv) angiogenesis, all being well established hallmarks of cancer.

During chronic inflammation, numerous intracellular signalling pathways are deregulated. For example, inflammation-driven deregulation of kinases such as JAK (Janus kinase) and MAPKs (mitogen-activated protein kinases) leads to transmission of growth signals that permit cellular acquisition of a malignant phenotype. Additionally, inflammation-induced aberrant activation of several transcription factors such as STAT3, NF-κB and HIF-1α (hypoxia-inducible factor-1α) has often been implicated in oncogenesis [2,9,11]. Deregulation of kinases coupled with aberrant activation of transcription factors consequently leads to the overexpression of numerous inflammatory mediators that play an essential role in generating the oncogenic switch. In the present review, we briefly discuss the potential role of inflammatory cells as well as important molecular players linking the process of chronic inflammation to that of cancer.

POTENTIAL DANGERS OF INHIBITING BENEFICIAL INFLAMMATION

Inflammation is the body's protective response against insult, intricately designed to restore tissue structure and function. Despite inflammation's causative link to tumorigenesis, it needs to be re-emphasized that inflammation is nonetheless essential to restore healthy normal tissue homoeostasis after infection or injury [2]. Specifically, acute inflammation is the healthy physiological response that is crucial for reinstatement of tissue structure and function. Following an insult, different subsets of leucocytes would be recruited to set the inflammatory process on the right path [12]. Chemokines and cytokines at the site of injury play a pivotal role in the recruitment of appropriate subsets of leucocytes to initiate and maintain the inflammatory response. Yet, what is crucial is the timely resolution of inflammation. Inflammation-resolution programmes include cytokine and eicosanoid switching from pro-inflammatory to anti-inflammatory and pro-resolution phenotypes respectively [12,13]. Thus it can be potentially harmful to completely inhibit inflammation in a bid to circumvent cancer. Instead, it is critical to understand that acute inflammation is contingent in re-establishment of tissue function and that it is chronic inflammation that arises owing to failure to resolve acute inflammation. Hence, in our opinion, strategies should be adapted to down-modulate the chronic inflammatory process instead of completely eliminating it. However, ideal pharmacological interventions remain far from reality, as inflammation is a complex and intricately orchestrated affair that involves a concerted effort from a wide range of pro- as well as anti-inflammatory molecules.

ROLE OF INFLAMMATORY CELLS IN ONCOGENESIS

Within the tumour microenvironment, leucocytes account for 50% of tumour mass, which mainly consists of lymphocytes and macrophages [10,14]. Macrophages are differentiated cells of circulating peripheral-blood monocytes, which migrate into tissues both at steady state and/or in response to inflammation. Macrophages demonstrate a high degree of plasticity where they are able to efficiently respond to an environmental stimulus and adapt with subsequent phenotypic alterations [10,14]. Most studies highlight only the two extreme ends of macrophage polarization: classically activated M1 macrophages and alternatively activated M2 macrophages [10,15]. Yet, macrophage polarization is an intricate affair, and clear distinct elucidation of this process is yet to be achieved. Demarcating macrophage polarization into two distinct populations does not take into consideration the subpopulation of macrophages that can evolve to exhibit characteristics that are shared by more than one macrophage population [16], thereby highlighting the need for a more informative macrophage classification scheme. Yet, this is easier said than done owing to the high degree of macrophage plasticity and its potential to rapidly respond to environmental stimuli (Figure 1).

A schematic representation of diverse functions of macrophages during inflammatory responses

Figure 1
A schematic representation of diverse functions of macrophages during inflammatory responses

In the presence of different environmental stimuli, macrophages can differentiate from monocytes in the peripheral blood into three different populations in the tissues; each population of macrophages has distinctive markers, as elegantly highlighted by Mosser and Edwards [16]. (i) When exposed to IFNγ and TNFα, monocytes differentiate to classically activated macrophages which produce high levels of IL-12 and low levels of IL-10. Additionally, they are able to secrete free radicals that contribute to the earlier stages of tumorigenesis. (ii) With changes in the inflammatory environment, new stimuli potentiate differentiation of monocytes into regulatory macrophages. Pre-existing classically activated macrophages can also further differentiate into regulatory macrophages. (iii) In the presence of IL-4, wound-healing macrophages are generated. They express resistin-like molecule α (RELMα), a unique molecule not expressed by the other two populations. Regulatory macrophages may also differentiate into wound-healing macrophages when treated with the appropriate environmental stimuli. LPS, lipopolysaccharide.

Figure 1
A schematic representation of diverse functions of macrophages during inflammatory responses

In the presence of different environmental stimuli, macrophages can differentiate from monocytes in the peripheral blood into three different populations in the tissues; each population of macrophages has distinctive markers, as elegantly highlighted by Mosser and Edwards [16]. (i) When exposed to IFNγ and TNFα, monocytes differentiate to classically activated macrophages which produce high levels of IL-12 and low levels of IL-10. Additionally, they are able to secrete free radicals that contribute to the earlier stages of tumorigenesis. (ii) With changes in the inflammatory environment, new stimuli potentiate differentiation of monocytes into regulatory macrophages. Pre-existing classically activated macrophages can also further differentiate into regulatory macrophages. (iii) In the presence of IL-4, wound-healing macrophages are generated. They express resistin-like molecule α (RELMα), a unique molecule not expressed by the other two populations. Regulatory macrophages may also differentiate into wound-healing macrophages when treated with the appropriate environmental stimuli. LPS, lipopolysaccharide.

Despite the lack of a unified scheme for macrophage classification, the role of macrophages in tumorigenesis is critical. Numerous reports highlight the direct link between TAM (tumour-associated macrophage) density and poor clinical outcome; where high TAM density correlates with increased incidences of angiogenesis, tumour invasion and metastasis [1720] in cancers such as liver [21], breast [22] and colorectal [23]. Moreover, by regulating activation and/or deactivation of numerous kinases, transcription factors and molecular mediators, TAMs consistently mediate the switch from chronic inflammation to tumorigenesis. A detailed analysis of the potential role of TAM in tumorigenesis would generally take into account two distinct populations of macrophages, as highlighted by Mosser and Edwards [16], the (i) classically activated macrophages, and (ii) regulatory macrophages (Figure 1). Previous reports highlighted that most TAMs within the tumour microenvironment possess a phenotype similar to M2 macrophages [24,25]; however, this is not entirely true. Despite their associated anti-proliferative and cytotoxic activity [26], classically activated macrophages also have the potential to contribute to the earlier stage of neoplasia [16]. Characterized not only by the production of high IL (interleukin)-12 and low IL-10 [15,25], classically activated macrophages also frequently produce free radicals [15,16] that can contribute significantly to DNA damage, causing mutations that can potentiate cellular transformation and subsequent tumorigenesis. Such oncogenic potential of classically activated macrophages was previously ignored and instead they were described to be entirely tumour-preventing [23] and cytotoxic to tumour cells [25,26]. Despite the existing contradictions in the literature, there is general consensus on the inflammatory phenotype of classically activated macrophages and their pivotal contribution to the process of tumorigenesis.

As tumours develop within the tumour microenvironment, there is generally a great deal of fluctuation within the tumour microenvironment. By responding to the changes in the environmental stimuli, macrophages adapt and change their physiology to resemble that of regulatory macrophages, characterized by low IL-12 and high IL-10 production [10,16,25]. Previously classically activated macrophages can progressively differentiate to a regulatory phenotype, which also displays characteristics of wound-healing macrophages. Wound-healing macrophages are another population of macrophages whose differentiation is stimulated by the presence of IL-4; similar to previously mentioned alternatively activated M2 macrophages [16]. Thus a high degree of macrophage plasticity demonstrates the complex nature of TAMs within the tumour microenvironment. The presence of TAMs within the tumour microenvironment is definitely a cause for great concern, as it can potentiate tumorigenesis by mediating angiogenesis, metastasis and immunosuppression (Figure 2).

Potential cross-talk between inflammatory mediators during cancer initiation and progression

Figure 2
Potential cross-talk between inflammatory mediators during cancer initiation and progression

Inflammation due to stress or infection when it becomes chronic can maintain the inflammatory state of TAMs. The uncontrolled production of oxidative stimuli, pro-inflammatory cytokines, MMPs, chemokines and growth factors in turn can lead to both initiation and progression of cancers. ECM, extracellular matrix; iNOS, inducible nitric oxide synthase.

Figure 2
Potential cross-talk between inflammatory mediators during cancer initiation and progression

Inflammation due to stress or infection when it becomes chronic can maintain the inflammatory state of TAMs. The uncontrolled production of oxidative stimuli, pro-inflammatory cytokines, MMPs, chemokines and growth factors in turn can lead to both initiation and progression of cancers. ECM, extracellular matrix; iNOS, inducible nitric oxide synthase.

TAMs are protagonists in tumour development via several distinct mechanism(s). First, TAMs contribute to angiogenesis [22], a process detailing the formation of new blood vessels from pre-existing blood vessels. Angiogenesis is crucial for sustained tumour development as it enables the tumour cells to not only acquire nutrients and oxygen, but also dispose of metabolic waste and carbon dioxide. An increase in TAM numbers correlates with an increase in tumour angiogenesis. By expressing mediators such as TGFβ (transforming growth factor β), VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor), MMPs (matrix metalloproteinases), TP (thymidine phosphorylase) and various chemokines, TAMs either directly or indirectly influence the angiogenic process [25]. For example, production of IL-1β by TAMs induces expression of HIF-1 by the tumour cells [27]. HIF-1 up-regulates the production of VEGF by TAMs, a key pro-angiogenic factor that leads to capillary formation. Besides possessing the ability to mediate the angiogenic process, TAMs facilitate the spread of tumour cells from the site of origin to a secondary site, a process known as metastasis. The metastatic ability of TAMs is derived from the production of a host of chemical stimulants, such as CCL18 (CC chemokine ligand 18) [28] which consequentially activates downstream pathways that can significantly enhance the metastatic property of tumour cells. Additionally, low IL-12 expression in TAMs demonstrates its poor immune-stimulatory property and antigen-presenting ability. Factors such as IL-10, PGE2 (prostaglandin E2), and TGFβ1 expressed by TAMs can contribute to decreased IL-12 expression, thereby suppressing both T-cell and NK (natural killer) cell proliferation and their associated cytotoxic effects [27]. Coupled with the production of mediators such as PGE2 and TGFβ, TAMs are undeniably agonists of immunosuppression [2932].

ROLE OF CHEMOKINES IN INFLAMMATION-RELATED CANCERS

Some of the most potent inducers of TAM recruitment are members of the chemokine family. Chemokines are a group of chemoattractant cytokines that are essential in the recruitment of leucocytes from the circulation to the site of inflammation. Depending on the position of the key cysteine residue, chemokines are grouped into four classes: C, CC, CXC and CX3C [2,33]. By binding to their cognate receptors, which are G-protein-coupled, chemokines are able to exert their innate function. At present, there are approximately 20 known chemokine receptors. Despite the small numbers, chemokines contribute significantly to the pathogenesis of inflammation-associated cancers. For example, pro-inflammatory chemokines have been demonstrated to play a role in the transition from intestinal inflammation to cancer [33], as well as lung inflammation to cancer [34].

As mentioned above, pro-inflammatory chemokines possess the ability to trigger leucocyte migration, a crucial function for the establishment of an inflammatory microenvironment that is required for eventual tumorigenesis in inflammation-associated cancers. Of the four subtypes of chemokines mentioned, the CC subtype is the most potent stimulant of leucocyte migration. Over the years, cumulated experimental data demonstrated the strong correlation between overexpression of CCL2 [MCP-1 (monocyte chemoattractant protein 1)] and CCL5 [RANTES (regulated upon activation, normal T-cell expressed and secreted)] and cancer progression (Figure 2). In patient breast and ovarian cancer biopsies, both CCL2 and CCL5 were overexpressed [35,36] and were demonstrated to be pivotal in monocyte recruitment, leading to eventual accumulation of TAMs at the tumour site.

Additionally, the roles of CCL2 and CCL5 have been investigated in experimental mice models where their chemokine levels were positively correlated with cancer cell proliferation, migration and metastasis [3739]. In addition, concomitant expression of both CCL2 and CCL5 was also demonstrated to be associated with advanced stages of breast cancer. Moreover, CCL5 was also demonstrated to up-regulate MMP9, which further contributes to tumour angiogenesis [37]. Hence it was proposed that effective treatment of breast malignancies requires inhibition of both CCL2 and CCL5 [36].

Besides the CC family of chemokines, the CXC family of chemokines also plays a role in cancer progression. The CXC chemokines, or α subgroup, are predominantly secreted by infiltrating inflammatory cells. CXC chemokines are heparin-binding proteins that possess the ability to either stimulate or inhibit angiogenesis depending on the presence of an ELR (Glu-Leu-Arg) motif [40]. CXC chemokines with the ELR motif (ELR+) promote angiogenesis, whereas CXC chemokines without the ELR motif (ELR) inhibit angiogenesis (i.e. are angiostatic) [33,40,41]. However, there is an exception to this: the ELR-CXC chemokine CXCL12 (CXC chemokine ligand 12)/SDF-1 (stromal-cell-derived factor-1), which binds to CXCR4 (CXC chemokine receptor 4) and CXCR7 and is implicated in both angiogenesis and metastasis [4143].

The presence of the ELR motif on CXC chemokines plays an important neutrophil regulating role. ELR+-CXC chemokines are chemoattractants of neutrophilic granulocytes, which in turn promote the angiogenic process [44]. Only recently did neutophils gain much attention. TANs (tumour-associated neutrophils) within the tumour microenvironment were only recently found to be associated with disease progression and severity [45]. Like TAMs, the TAN number is also able to provide a prognostic overview of the patient disease condition. For example, Rao et al. [46] demonstrated that infiltration of intratumoral neutrophils in CRC (colorectal carcinoma) is indicative of poor prognosis and tumour progression, which requires utilization of more aggressive treatments.

TANs, particularly the tumour-promoting N2 phenotype, are drawn towards diseased sites via the chemoattractant property of chemokines. The CXCL that binds to either the CXCR1 or CXCR2 transmembrane GPCR (G-protein-coupled receptor) expressed on the surface of neutrophils is responsible for the homing of TANs to disease sites [45]. Namely, CXCL1-8 binds to CXCR2, with CXCL6 and CXCL8 being able to bind to both CXCR1 and CXCR2 [41,45]. In HCC (hepatocellular carcinoma) derived predominantly from inflamed cirrhotic liver, CD15 neutrophil recruitment by CXCL1, CXCL2, CXCL3 and CXCL8 has been found to correlate with poor patient survival [45]. Additionally, using HCC patient-derived cells, Kuang et al. [47] demonstrated that neutrophil infiltration correlates with an increase in VEGF expression, inevitably potentiating angiogenesis at tumour sites.

In addition to TAN recruitment, CXC chemokines released by TAMs are also capable of promoting tumour metastasis. The CXCR4/CXCL12 axis is a well-documented CXC chemokine whose expression level correlates not only with tumour stage and aggressiveness, but also with overall poor patient prognosis, and has also been associated with chemoresistance [48]. The CXCR4/CXCL12 axis is implicated in both angiogenesis and metastasis in breast [17,49], brain [50], ovarian [51] and colorectal [33,52] cancer. Metastasis is achieved via CXCR4/CXCL12-directed up-regulation of MMP, which aids in metastasis via degradation of the basement membrane [41]. Despite CXCR4/CXCL12’s role in oncogenesis, we cannot discount its pivotal role in normal embryonic development. CXCR4−/− mice exhibited impaired haemopoiesis, heart and brain developmental defects, and defective vascularization, whereas the CXCR4−/−CXCL12−/− double knockout is lethal and these embryos die in utero [53].

ROLE OF CYTOKINES IN INFLAMMATION-DRIVEN CANCERS

Cytokines are low-molecular-mass proteins that orchestrate a host of physiological processes. Without doubt, cytokines are a double-edged sword, as they possess the ability to either stimulate and aggregate inflammation or attenuate inflammatory responses. Pro-inflammatory cytokines, especially interleukins and TNFα (tumour necrosis factor α), have been well demonstrated to contribute to inflammation-associated carcinogenesis [5456] (Figure 2). Although anti-inflammatory cytokines such as IL-4 and IL-10 do not contribute to the inflammatory pathogenesis of inflammation-associated cancer, aberrant regulation of anti-inflammatory cytokines may still consequentially contribute to tumorigenesis; for example, aberrant regulation of IL-10 has been associated with poor prognosis in pancreatic [57] and lung [58] cancers.

An imbalance between host-mediated anti-tumour activity and tumour-mediated immunosuppressive activity has dire consequences, especially when the latter triumphs over the former. One of the key hallmarks of cancer is that tumour cells are able to escape immunosurveillance, thereby enabling tumour cells to evade apoptosis and achieve eventual invasion and metastasis to nearby or distant organs/tissues [54]. Immunosuppression and eventual tumour cell migration and invasion is achieved with the secretion of a host of chemokines and cytokines by both tumour and immune cells within the tumour microenvironment [59]. Metastatic and invasive potential is achieved via the enhanced production of MMP-7 by TAMs, whose expression is up-regulated by the increased secretion of TNFα by tumour cells. Besides conferring metastatic and invasive properties to tumour cells, MMP-7 increases chemoresistance and decreases apoptotic sensitivity of tumour cells [5961], thereby enabling the population of tumour cells to thrive within the tumour microenvironment.

Although IL-10 is an anti-inflammatory cytokine, there exist numerous reports that highlight its potential immunosuppressive role in tumorigenesis [58,62]. IL-10 down-regulates the expression of pro-inflammatory cytokines, thereby limiting tissue damage caused by inflammatory stimuli. However, excessive IL-10 production can also upset the fine balance between pro-inflammatory and anti-inflammatory cytokines, thereby potentiating tumorigenesis by exerting its immunosuppressive ability. Autocrine production of IL-10 contributes to defective expression of IL-12, a cytokine required for the maintenance of cell-mediated immunity [63,64]. As discussed above, high IL-10 and low IL-12 signals induce differentiation of macrophages to regulatory macrophages, a population of macrophages present within an established tumour microenvironment [10,16,25]. Also, experiments by Zeng et al. [58] have demonstrated that IL-10 overexpression in lung tumour cell lines can contribute to a significant increase in metastatic potential via increasing the angiogenic capacity of tumour cells while decreasing their apoptotic capacity. Hence, despite its reported anti-inflammatory function, IL-10 still possesses the capability to potentiate tumorigenesis via inducing immunosuppression, differentiation of macrophages and conferring metastatic as well as angiogenic capacity on tumour cells.

In contrast, pro-inflammatory cytokines play a crucial role in linking the process of chronic inflammation to that of cancer. The IL-6 family of cytokines are considered the linchpins between inflammation and cancer, whose expression, if perturbed, can consequentially lead to tumoristatic/tumoricidal effect. Within the IL-6 family of cytokines, which includes IL-11, IL-27, IL-31, LIF (leukaemia-inhibitory factor), OSM (oncostatin M), CNTF (ciliary neutrophic factor), CT-1 (cardiotrophin-1) and CLC (cardiotrophin-like cytokine) [56], IL-6 and IL-11 are the dominant pro-inflammatory cytokines that are well studied for their complex role in tumorigenesis. IL-6 and IL-11 transduce their signals by forming a hexameric complex of two ligand molecules, two molecules of α receptors [IL-6Rα (IL-6 receptor α) and IL-11Rα (IL-11 receptor α)] and two molecules of gp130 (glycoprotein 130) [65]. Activation of the gp130 receptor by IL-6 and/or IL-11 can activates various oncogenic signalling cascades such as Ras/ERK (extracellular-signal-regulated kinase), JAK/STAT3 and PI3K (phosphoinositide 3-kinase)/Akt, all of which can induce cell proliferation, survival, invasion, metastasis, angiogenesis and inflammation, inevitably leading to the creation of a tumour microenvironment. Interestingly, IL-6 has also been found to promote proliferation and survival of pre-malignant intestinal epithelial cells in colitis-associated tumorigenesis [66]. Besides IL-6’s role in colitis-associated tumorigenesis, IL-6 is also elevated in many other cancers such as skin, breast, lung, oesophageal, liver, pancreatic, gastric, prostate, kidney, bladder, melanoma and haematological cancers [56]. As such, IL-6 and its related cytokines are considered to be critical linchpins between inflammation and cancer.

Both IL-6 and IL-11 promote not only cell proliferation, survival and differentiation, but also invasion, angiogenesis and metastasis. IL-6 overexpression inevitably leads to constitutive activation of the JAK/STAT3 pathway [67] (Figure 2). Phosphorylation, and therefore activation, of STAT3 up-regulates expression of cyclins while down-regulating the expression of the Cdk (cyclin-dependent kinase) inhibitor p21, thereby promoting cell proliferation [56,68,69]. Additionally, STAT3 activation leads to chemoresistance because its constitutive expression increases the expression of survival proteins such as survivin [56,69,70].

The IL-6 family of cytokines also contributes to the generation, maintenance and migration of stem/progenitor cells, including CSCs (cancer stem cells). In several human cancers such as lung, breast, stomach, colon, liver, gall bladder and pancreatic carcinoma, LIF is produced to maintain stem/progenitor cells in an undifferentiated state [56]. Besides LIF, IL-6 itself is implicated in breast cancer development and progression. First, induction of IL-6 by monocyte-derived CCL2 drives a feedforward inflammatory signalling pathway. This feedforward pathway leads to constitutive IL-6 production, and drives breast cancer cell transformation and tumorigenesis [71]. Additionally, IL-6 possesses the ability to enhance the recruitment of bone-marrow-derived mesenchymal stem cells to sites of developing breast tumours and stimulate production of chemokines, which enhances further the proliferation of breast CSCs [72]. Expansion of the breast CSC population creates an issue from a therapeutic standpoint as breast CSCs are the subset of cells that demonstrate chemo- and/or radio-resistance and are responsible for relapse following therapy [73,74].

Overexpression, and hence high serum levels, of IL-6 in human cancer not only is associated with advanced stages of cancer, but also correlates with poor prognosis [57,68]. Epithelial cells obtained from biopsy samples of patients diagnosed with colitis-associated colorectal cancer were stained for IL-6, pSTAT3 and SOCS3 (suppressor of cytokine signalling 3), which inhibit JAK/STAT signalling. Positively stained IL-6 and pSTAT3 cells positively correlate with, and SOCS3 staining negatively correlates with, colitis-associated colorectal cancer progression [9]. Additionally, serum IL-6 levels in stomach, liver, pancreatic, lung, oesophagus, mammary gland, uterus, ovary, prostate, kidney and bladder cancer were also reported to be associated with either advanced stage of disease and/or poor prognosis [56].

Another cytokine that has been relatively well studied for its potential tumorigenic role is IL-1β. High concentrations of IL-1β have been reported to be associated with poor prognosis in cancers such as melanomas, and colorectal, lung, head and neck [75]. IL-1β is a key player in inflammation-associated cancers as it regulates expression of several proteins involved in the inflammatory processes (for example, the transcription factor NF-κB) [76]. By up-regulating the expression of tumorigenic genes, IL-1β creates a microenvironment that favours tumorigenesis. The tumorigenic role of IL-1β has been demonstrated in knockout mice. In these IL-1β-deficient mice, tumorigenesis was reported to be much slower and less compared with the WT mice [76,77]. Hence IL-1β could be a potential therapeutic target to cause a reduction in tumour growth.

In addition, TNFα also contributes significantly to the process of tumorigenesis. TNFα has been reported to be produced by a variety of tumour cells, including those of lung, colorectal, pancreatic [78,79] and breast [80] cancers. Interestingly, TNFα contributes not only to sustained chronic inflammation, but also to tumour initiation, development and progression. Myeloid-cell-derived TNFα promotes inflammation-associated tumours [81], whereas macrophage-derived TNFα has been implicated in inflammation and subsequent tumorigenesis [55,82]. Additionally, using in vivo mouse models, Sade-Feldman et al. [83] demonstrated that TNFα has an immunomodulating ability. By blocking maturation and differentiation of MDSCs (myeloid-derived suppressor cells) into dendritic cells and macrophages, coupled with enhancement of the suppressive function of MDSCs by stimulating production of iNOS (inducible nitric oxide synthase) and arginase 1, TNFα promotes the immunosuppressive environment generated during chronic inflammation [83].

Moreover, serum levels of TNFα serve as a predictor of patient survival. For instance, TNFα in CLL (chronic lymphocytic leukaemia) patients was found to be significantly higher compared with the control population, and serves as a predictor of patient survival [84]. Additionally, increased tumour expression of TNFα together with other pro-inflammatory interleukins in prostate cancer was significantly correlated with poor prognosis and with prostate cancer progression [85]. However, it is crucial to note that TNFα has a paradoxical role as it can function as both a tumour necrosis factor and a tumour-promoting factor [86,87]. When administered continuously at high doses directly into the tumour mass, TNFα resulted in growth inhibition of established tumours in human xenograft models [88]. Conversely, TNFα treatment of experimental ascitic ovarian cancer xenografts renders TNFα a tumour-promoting factor as it promoted peritoneal adhesion and solid tumour formation [89]. Additionally, daily administration of thalidomide, an inhibitor of TNFα, demonstrated a reduction in the volume of ascites, number of peritoneal and distant deposits, and increased paclitaxel cytotoxicity in an ovarian cancer xenograft model [90,91]. Hence, despite the dual role of TNFα, novel strategies that neutralize TNFα may actually be useful in cancer therapy.

ROLE OF TRANSCRIPTION FACTORS IN INFLAMMATION-MEDIATED CANCERS

Pro-inflammatory transcription factors such as NF-κB and STAT3 are critical mediators of inflammation-related cancer [6]. These transcription factors modulate the inflammatory response and promote tumorigenesis via production/recruitment of soluble mediators such as cytokines (e.g. IL-6), chemokines (e.g. CCL2), and other cellular components (e.g. TAMs) [92,93]. NF-κB is a well-documented transcription factor that plays a critical role in the establishment of a chronic inflammatory state and eventual progression towards tumorigenesis [9497]. NF-κB exists as homo/hetero-dimers derived from five distinct subunits: RelA (p65), RelB, c-Rel, p50 (NF-κB1) and p52 (NF-κB2) [97,98]. Owing to NF-κB's binding to the IκB (inhibitor of NF-κB) family of proteins that prevents NF-κB–DNA binding and nuclear accumulation, the majority of NF-κB dimers are predominantly cytoplasmic [2,98100]. Comparatively, activated NF-κB is present in the nucleus and binds to the promoter region of its target genes [6,101,102].

Using a murine cancer metastasis model of colon adenocarcinoma, Luo et al. [103] demonstrated that LPS (lipopolysaccharide)-induced metastatic growth is dependent not only on TNFα production by haemopoietic cells, but also on NF-κB activation by tumour cells [103]. Constitutively active NF-κB is present in most cancers and chronic inflammatory conditions. Activation of NF-κB in response to extracellular stimuli, such as cytokines, requires cleaving of the IκB moiety from the NF-κB–IκB complex via a canonical IKK (IκB kinase) complex-dependent pathway or a non-canonical NF-κB-inducing kinase pathway [5]. NF-κB expression is tightly regulated because aberrant expression not only contributes to cellular proliferation via regulation of genes encoding proteins important for cell cycle progression and anti-apoptotic pathways, but also has been linked to chemoresistance and radioresistance [2,6,8,104].

Whereas constitutive NF-κB activation contributes to chemoresistance and radioresistance, NF-κB suppression leads to sensitization of tumour cells to chemotherapeutic agents and γ-irradiation. For instance, inhibition of NF-κB by obovatol, an active biphenolic component in Magnolia obovata, inhibited prostate and colon cancer cell growth [105]. NF-κB inhibition inevitably halted anti-apoptotic gene expression and therefore contributed to eventual induction of apoptotic cell death [96,106]. Similarly, expression of a dominant-negative mutant IκB in human head and neck squamous cell carcinoma inhibited survival, pro-inflammatory cytokine expression and tumour growth in vivo [2,6].

STAT3 is also constitutively activated in several cancers [67]. Upon stimulation by EGF (epidermal growth factor) and IL-6, STAT3 is phosphorylated (i.e. pSTAT3) and homodimerizes before nuclear translocation [67]. STAT3 works in close liaison with NF-κB to mediate the link between inflammation and tumour initiation, progression and development. Using loss- and gain-of-function mice in a colitis-associated colorectal cancer model, Bollrath et al. [66] established a link between gastrointestinal cancer and chronic inflammation that is involved in STAT3 signalling [69]. Persistent activation of STAT3 has been documented to not only promote cellular proliferation by regulating genes associated with cell cycle progression, but also have the ability to promote tumour angiogenesis, resistance to apoptosis [67,107] and immunosuppression [69,108].

Similar to NF-κB inhibition, STAT3 inhibition potentiates anti-tumour activity. Andrographolide, a natural bicyclic diterpenoid lactone, was demonstrated to be able to induce cell cycle arrest and apoptosis of pancreatic cancer cells. By inhibiting STAT3 and Akt activation, up-regulating expression of p21WAF1 and BAX, and down-regulating expression of genes promoting cell cycle progression, andrographolide exhibited efficacious anti-tumour activity in vivo using nude BALB/c mice [109]. Additionally, another natural inhibitor obtained from the Chinese medicinal plant Tripterygium wilfordii, celastrol, was found to inhibit proliferation and induce apoptosis in HCC cells via inhibition of STAT3 activation [110]. Celastrol led to suppression of various gene products involved in proliferation, survival and angiogenesis. As such, both NF-κB and STAT3 can be considered attractive molecular targets for treating and preventing chronic inflammation-driven cancers.

ROLE OF ENZYMES IN INFLAMMATION-RELATED CANCER

There are several enzymes that mediate the progression from inflammation to cancer. Chronic inflammation triggers the production of inflammatory molecular mediators (i.e. chemokines, cytokines and growth factors), which in turn activates inflammatory pathways that lead to tumour initiation, progression and development [111]. The COX (cyclo-oxgenase) pathway is one of the signalling pathways implicated and, more recently, telomerase has also been found to contribute to tumorigenesis. There exist two major COX isoforms, COX-1 and COX-2, whose expression is variable between tissues. COX-1 is responsible for the homoeostatic balance of prostanoid production, whereas COX-2 is often referred to as the rate-limiting isoform [111]. COX-2 is undetectable in most normal tissues, is responsible for prostanoid production during inflammation and is markedly up-regulated in cancers. For example, overexpression of COX-2 has been shown to regulate colorectal cancer-induced angiogenesis [2]. Additionally, elevated levels of PGE2, an enzymatic product of COX-2, has been found in various cancers such as colorectal, lung, breast, head and neck, and oesophageal [112].

Several studies have demonstrated that up-regulation of COX-2, and its enzymatic product PGE2, is associated with tumour progression and development. Elevated levels of PGE2 correlate with poor prognosis, where the survival rate decreases with an increase in COX-2 expression [2,111]. Such an inverse relationship between COX-2 levels and survival rate can be attributed to the production of proteins that aid with proliferation, resistance to apoptosis, chemo/radio-resistance and/or establishment of other hallmarks of cancer. For instance, in NSCLC (non-small-cell lung cancer) cell lines and a mouse lung cancer model, up-regulation of COX-2 inevitably induced overexpression of MRP4 (multidrug-resistance protein 4) [113]. Consequently, lung cancer cells acquire resistance to many chemotherapeutic agents, as is evident from clinical data that demonstrate several instances of multidrug-resistant lung cancers [111,114].

In recent years, more light has been shed on the pivotal role of telomerase in inflammation-related cancer [115]. By directly regulating NF-κB-dependent gene expression, telomerase imparts to tumour cells the ability to proliferate and resist apoptosis [104], inevitably contributing to tumorigenesis. Expression of the telomerase subunit TERT (telomerase reverse transcriptase) can cause rapid cell proliferation in some human and murine cell lines. Additionally, TERT overexpression confers immortality on human fibroblasts, which in turn secrete epiregulin, a growth factor belonging to the EGF family that enhances cell growth. With TERT, cells are also able to bypass differentiation where telomerase-mediated activation of Wnt signalling has been shown to suppress differentiation and induce proliferation [116].

TERT has also been reported to modulate angiogenesis, as well as invasion and metastasis. For instance, cells transfected with siRNA against TERT demonstrated reduced production of pro-angiogenic factors against control groups [116]. Also, Liu et al. [117] demonstrated that TERT overexpression promotes EMT (epithelial–mesenchymal transition), which confers migratory and invasive ability on cells [117]. Finally, TERT also regulates NF-κB expression. NF-κB has been shown to be critical for EMT and is also required for MMP-9 expression, both of which are critical for metastasis. Reactivated TERT/telomerase sustains enhanced NF-κB activity, creating a feedforward loop in which telomerase works in unison with p65 on a subset of target gene promoters, inevitably sustaining inflammation and promoting tumorigenesis [104]. A schematic diagram illustrating the potential role of various key molecular players in the process of chronic inflammation driven cancers is shown in Figure 2.

ROLE OF OXIDATIVE STRESS IN INFLAMMATION-RELATED CANCER

Damage of important biomolecules and cells occurs when there is an imbalance between production of free radicals and reactive metabolites, commonly referred to as oxidants or ROS (reactive oxygen species) [118]. Under normal physiological conditions, ROS are generated in cells by the mitochondrial respiratory chain and play a vital role in the regulation of signalling pathways in response to changes in cellular environmental conditions [119]. Under aerobic environments, cells produce ROS such as superoxide anion, hydrogen peroxide, hydroxyl radical and organic peroxides as normal products of reduction of molecular oxygen [120]. Conversely, under hypoxic conditions, nitric oxide is produced, which can generate RNS (reactive nitrogen species) [121]. Although ROS are required for cellular signalling events, sustained production of ROS can cause significant damage to cell structure and function, thereby potentially inducing mutations and/or neoplastic transformation [122,123]. Purine and pyrimidine bases as well as sugar moieties of DNA can be adversely affected by ROS/RNS. Oxidatively induced DNA lesions can be repaired by DNA repair pathways such as BER (base-excision repair) and NER (nucleotide-excision repair) [93]. However, there may be instances when DNA lesions are not repaired or when DNA lesions occur to a large extent and, as a result, cumulative DNA damage may inevitably lead to tumorigenesis. In inflammation-related cancers, chronic inflammation potentiates the production of ROS by immune cells [2]. Additionally, it has also been observed that tumour promoters can recruit and stimulate inflammatory cells to generate ROS/RNS, thereby generating DNA lesions and subsequently inducing mutations [124]. In turn, these mutations can potentiate tumorigenesis, thereby creating a vicious cycle of ROS/RNS production within the tumour microenvironment. In fact, oxidative stress can interact with all three stages of cancer, including initiation, promotion and progression (Figure 2). During cancer initiation, ROS/RNS generate DNA lesions, thereby introducing gene mutations and structural alterations into the DNA [118,125]. During cancer promotion, ROS/RNS contribute to abnormal gene expression resulting in an increase in cell proliferation and a contrasting decrease in apoptosis; thereby generating a tumour microenvironment favourable for cancer progression [122,126,127]. Finally, oxidative stress can also contribute to cancer progression via addition of further DNA alterations to the initiated stem cell population. Additionally, ROS/RNS mediate cancer development and progression by conferring proliferative, invasive, angiogenic and chemoresistance properties on the initiated stem cell population [118,122,124,126,128].

PHARMACOLOGICAL ABROGATION OF INFLAMMATORY MEDIATORS

Despite numerous studies on the effect of various pharmacological agents targeting deregulated inflammatory cascades in tumour cell lines and mouse models, there are only a few drugs that have been approved by the U.S. FDA (Food and Drug Administration) for therapeutic use in patients. For example, tocilizumab is a humanized monoclonal antibody against IL-6R that is sold under the trade name of either Actemra or RoActemra. Tocilizumab is an immunosuppressive drug that was approved in 2010 for the treatment of RA (rheumatoid arthritis). RA is an inflammatory condition that has been linked to lung cancer via the COX-2/TxA2 (thromboxane A2) pathway [129]. Within the RA inflammatory microenvironment, inflammatory cytokines such as IL-6 are produced. IL-6, together with other inflammatory mediators, generates an autoregulatory feedback loop for the COX-2/TxA2 pathway, inevitably increasing expression of COX-2 and its upstream and downstream molecules [i.e. PGE2, PLA2 (phospholipase A2) and TxA2]. Hence inhibition of IL-6R by tocilizumab can potentially down-regulate COX-2 expression as well as its respective upstream and downstream molecules, and thereby decrease the risk of lung cancer in RA patients.

Another treatment approach for cancer is to inhibit proteasome activity. In 2003, the FDA approved the first proteasome inhibitor, bortezomib, for treatment of MM (multiple myeloma) and mantle cell lymphoma. Inhibiting proteasome activity leads to an increase in pro-apoptotic factors within the tumour microenvironment, in the hope that this would activate programmed cell death of tumour cells. However, with exposure to a single chemotherapeutic agent, there runs a risk of overactivation of a survival pathway, thereby decreasing drug efficacy. To combat decreased drug efficacy and resistance, combination therapies can be adopted. For example, thalidomide–bortezomib combination therapy has been investigated for the treatment of MM. Such combination therapy has been shown to improve the clinical outcome of MM patients [130]. However, when adopting a combination therapy strategy, it is important to closely monitor the drug response because such therapeutic strategies are associated with toxicity complications [131,132].

In colorectal cancer tissues, increased TNFα expression correlates with increased expression of MET and HGF (hepatocyte growth factor) [133]. The ligand–receptor pair of HGF–MET is associated with tumorigenic states and regulates invasive growth programs. Hence, down-regulation of TNFα could possibly deter invasion and metastasis. There exist several TNFi (TNFα inhibitors) in the market: infliximab, adalimumab, certolizumab pegol and golimumab, all of which are monoclonal antibodies against TNFα. However, these drugs are mainly employed not for the treatment of cancer, but for RA [134]. Experiments using TNFi on tumour cell lines yielded contrasting results. For example, Hamaguchi et al. [87] demonstrated that by inhibiting TNFα binding to its receptors, TNFi suppresses bone metastasis in breast cancer cell lines. In contrast, in a systemic review and meta-analysis conducted by Bongartz et al. [135], it was found that infliximab and adalimumab administration in RA patients is associated with an increased risk of infections and malignancies. Hence, despite being a potential cancer therapeutic option, TNFi tumoricidal/tumoristatic potential needs to be studied in greater detail in order to deter risk of infections and to prevent potentiating tumorigenicity upon administration in cancer patients.

Finally, there are also FDA-approved drugs that target several oncogenic molecular targets. An example is thalidomide, a glutamic acid derivative first synthesized in 1953. The initial prescription of thalidomide was for epilepsy treatment. However, FDA approval for the use of thalidomide for cancer treatment was only obtained in 2006. Although the exact mechanism of action of thalidomide remains unclear, it is reported that thalidomide possesses immunomodulatory, anti-inflammatory and anti-angiogenic effects. For instance, thalidomide has been experimentally demonstrated to regulate not only inflammatory cytokines such as TNFα, IL-12 and IL-10, but also enzymes such as COX-2 and transcription factors such as NF-κB. In MM patients, treatment with thalidomide is accompanied by an increase in the circulation of natural killer cells and plasma levels of IL-2 and IFNγ (interferon γ) which are associated with cytotoxic activity [136]. Additionally, thalidomide is used in combination therapy such as thalidomide–bortezomib [130], thalidomide–dexamethasone [137] and statin–thalidomide [138] to increase tumoristatic/tumoricidal efficiency and possibly combat chemoresistance associated with single drug administration.

In addition, corticosteroids, such as glucocorticoids, possess both immunosuppressive and anti-inflammatory properties [139] and are mainly employed for palliative purposes. By binding to glucocorticoid receptors, glucocorticoids are able to down-regulate transcription of pro-inflammatory mediators and up-regulate expression of anti-inflammatory mediators. The anti-inflammatory property of glucocorticoid is mainly mediated by the synthesis of annexin A1, a glucocorticoid-induced molecule [117]. Glucocorticoids are frequently prescribed for treatment and/or management of inflammatory disorders such as asthma [140], RA [141] and multiple sclerosis [142]. Glucocorticoids exhibit significant anti-prostate cancer activities and function as anti-growth and anti-metastatic agents against metastatic castration-resistant prostate cancer [143,144]. It also significantly relieves pain due to bone metastasis in prostate cancer patients. Interestingly, glucocorticoids are co-administered with standard chemotherapy to treat several cancers [145]. Corticosteroids have considerable neuropsychiatric adverse effects and thus have to be used with significant caution for management of inflammatory disorders and cancers [146]. Overall, the drugs discussed above are associated with major side effects which may circumvent their beneficial effects when administered to patients. A partial list of FDA-approved drugs currently being employed for the treatment of inflammatory diseases and cancers is shown in Table 1.

Table 1
A list of selected FDA-approved drugs for the clinical management of inflammatory diseases and cancers
Drug name Type Target(s) Indication(s) Reference(s) 
Tocilizumab Humanized monoclonal antibody IL-6R Rheumatoid arthritis; Castleman disease [68
Bortezomib Proteasome inhibitors Chymotrypsin-like catalytic subunit of proteasome Mantle cell lymphoma, relapsed multiple myeloma [130
Carfilzomib  Threonine residue of the catalytic subunit of proteasome Multiple myeloma with at least two prior therapies [186,187
Etanercept Fusion protein produced from recombinant DNA of TNFα receptor and IgG1 Fc region TNFα Rheumatoid arthritis [188
Infliximab Chimaeric monoclonal antibody  Crohn's disease, ulcerative colitis [87,134,189
Adalimumab Human monoclonal antibody  Ankylosing spondylitis, Crohn's disease, psoriatic arthritis, plaque psoriasis, rheumatoid arthritis, ulcerative colitis  
Certolizumab Pegol Humanized monovalent Fab antibody fragment linked to poly(ethylene glycol)  Crohn's disease, psoriatic arthritis  
Golimumab Human monoclonal antibody  Rheumatoid arthritis, ulcerative colitis  
Thalidomide Multi-targeted Inhibits TNFα, IL-6, IL-10 and IL-12 production; enhances the production of IL-2, IL-4 and IL-5 by immune cells; abrogates NF-κB and COX-2 activity Multiple myeloma [90,130,136138
Dexamethasone Corticosteroids Glucocorticoid receptor Diabetic macular oedema, multiple myeloma (for pain relief), non-infectious uveitis, ovarian cancer [139,190
Hydrocortisone   Crohn's disease; leukaemia; lymphoma; multiple myeloma [139,191
Methylprednisolone   Rheumatoid arthritis [139
Drug name Type Target(s) Indication(s) Reference(s) 
Tocilizumab Humanized monoclonal antibody IL-6R Rheumatoid arthritis; Castleman disease [68
Bortezomib Proteasome inhibitors Chymotrypsin-like catalytic subunit of proteasome Mantle cell lymphoma, relapsed multiple myeloma [130
Carfilzomib  Threonine residue of the catalytic subunit of proteasome Multiple myeloma with at least two prior therapies [186,187
Etanercept Fusion protein produced from recombinant DNA of TNFα receptor and IgG1 Fc region TNFα Rheumatoid arthritis [188
Infliximab Chimaeric monoclonal antibody  Crohn's disease, ulcerative colitis [87,134,189
Adalimumab Human monoclonal antibody  Ankylosing spondylitis, Crohn's disease, psoriatic arthritis, plaque psoriasis, rheumatoid arthritis, ulcerative colitis  
Certolizumab Pegol Humanized monovalent Fab antibody fragment linked to poly(ethylene glycol)  Crohn's disease, psoriatic arthritis  
Golimumab Human monoclonal antibody  Rheumatoid arthritis, ulcerative colitis  
Thalidomide Multi-targeted Inhibits TNFα, IL-6, IL-10 and IL-12 production; enhances the production of IL-2, IL-4 and IL-5 by immune cells; abrogates NF-κB and COX-2 activity Multiple myeloma [90,130,136138
Dexamethasone Corticosteroids Glucocorticoid receptor Diabetic macular oedema, multiple myeloma (for pain relief), non-infectious uveitis, ovarian cancer [139,190
Hydrocortisone   Crohn's disease; leukaemia; lymphoma; multiple myeloma [139,191
Methylprednisolone   Rheumatoid arthritis [139

RESEARCH PERSPECTIVES

In the last few years, our group has also identified several small-molecule pharmacological inhibitors that have exhibited significant NF-κB/STAT3 inhibitory effects in diverse tumour cell lines and pre-clinical cancer models [67,69,147]. Inhibition of NF-κB/STAT3 has garnered much attention in the last few decades as cumulative evidence highlights that constitutive activation of these two transcription factors plays a pivotal role in cancer initiation, development and progression [148150]. Thus identification of novel small molecules derived from natural sources that display potent anti-cancer effects with lower toxicity profiles than synthetic drugs as discussed above may form the basis of novel therapy for cancer patients. The chemical structures of a selected few of such dual inhibitors are shown in Figure 3 and their potential anticancer effects are discussed in brief below.

Chemical structures of selected natural agents acting as dual inhibitors of STAT3/NF-κB transcription factors

Figure 3
Chemical structures of selected natural agents acting as dual inhibitors of STAT3/NF-κB transcription factors

These pharmacological agents exert their anti-cancer effects primarily by blocking STAT3/NF-κB signalling cascades by pleiotropic mechanisms in tumour cells and pre-clinical models.

Figure 3
Chemical structures of selected natural agents acting as dual inhibitors of STAT3/NF-κB transcription factors

These pharmacological agents exert their anti-cancer effects primarily by blocking STAT3/NF-κB signalling cascades by pleiotropic mechanisms in tumour cells and pre-clinical models.

Butein

Butein, a tetrahydroxychalcone derivative, has been found to abrogate both NF-κB [151] and STAT3 [152] activation cascades. Our team demonstrated the ability of butein to inhibit proliferation and enhance the apoptotic effect of paclitaxel and doxorubicin in HCC cells. [152]. Also, butein caused substantial suppression of STAT3 activation as well as expression of various oncogenic genes such as those encoding cyclin D1, Bcl-2, survivin and VEGF [152]. Finally, butein treatment induced inhibition of the growth of HCC xenograft tumours in mice [152]. Combined with studies reported by other groups, it was noted that butein possesses not only anti-proliferative and apoptotic properties, but also anti-metastatic [153] properties. Additional toxicity and pharmacokinetic studies need to be conducted before butein can be tested under clinical settings in cancer patients.

Capsaicin

Present in hot red and green chilli peppers, capsaicin is an alkaloid that has been traditionally utilized to alleviate neuropathic pain and itching in humans [154,155]. Capsaicin exerts its anti-cancer properties via interaction of the vanilloid ring with TRPV (transient receptor potential vanilloid) channels [156,157]. Similar to butein, capsaicin was found to inhibit STAT3 and down-regulate expression of STAT3-regulated gene products [158]. However, caution must be taken when dealing with administration of capsaicin, as studies have shown that administration of high doses of this agent for a prolonged period not only causes peptic ulcers, but also accelerates the development of prostate, stomach, duodenal and liver cancers and can enhance the metastatic rate of breast cancer [156,159].

Celastrol

Celastrol, derived from the Chinese medicinal plant Tripterygium wilfordii, has been demonstrated to possess anti-cancer effects [158,160]. Our group has demonstrated celastrol's anti-cancer effects on HCC cell lines and in vivo tumour models. Indeed, celastrol was able to inhibit both constitutive and inducible STAT3 expression in various HCC cell lines and inhibited the tumour growth in a xenograft mouse model [110]. Also, this triterpene was reported to substantially abrogate constitutive NF-κB as well as STAT3 activation in MM cells [160]. Coupled with data from previous pre-clinical studies that utilized celastrol in the management of various inflammatory disease and cancer models, this triterpene was generally found to be well-tolerated without exhibiting significant side effects.

Diosgenin

Diosgenin, a steroidal saponin found in a variety of plants such as wild yam (Dioscorea villosa), was first demonstrated by our group to inhibit the STAT3 signalling pathway in HCC cell lines [161]. It has been demonstrated in vitro and in vivo that the spiroketal ring of diosgenin is the essential structural component required for diosgenin's anti-inflammatory and anti-cancer properties [162]. Similar to celastrol, diosgenin was found to suppress not only STAT3 activation, but also the expression of diverse NF-κB-regulated oncogenic genes [163]. However, additional pre-clinical studies are needed to validate the safety profile of diosgenin before it can be tested in patients.

Thymoquinone

A substance found in black seed oil, thymoquinone has been found by our group to possess an unique ability to overcome chemoresistance and enhance the effect of bortezomib treatment in MM cell lines and mouse models [164]. Although the mechanism underlying chemoresistance has yet to be clearly elucidated, one of the main contributors to chemoresistance is thought to be aberrant activation of NF-κB/STAT3 pathways [165]. Unlike conventional chemotherapy agents, thymoquinone has been extensively studied in diverse tumour models and demonstrates efficacy against tumour cells through suppression of both NF-κB and STAT3 without exhibiting significant toxic effects towards normal cells [164,166].

Resveratrol

Found in abundance in red grapes, berries and peanuts, resveratrol is a polyphenol that has been well demonstrated to exhibit pleiotropic anti-cancer effects. Found commonly in a trans-configuration, resveratrol has been found to have low toxicity without exerting adverse effects in humans even when administered at high doses [167]. Through inhibition of predominantly NF-κB/STAT3 activation pathways, resveratrol's anti-cancer properties have been established in several cancers such as those of breast [168170], prostate [171], liver [172], thyroid [173] and cervix [174]. Resveratrol not only exhibited significant anti-proliferative effects, but also induced apoptosis primarily through down-regulation of the NF-κB/STAT3 pathway in MM cells [165]. Additionally, resveratrol was also demonstrated to significantly potentiate the apoptotic effect of bortezomib and thalidomide [165], two commonly utilized standard chemotherapy options for MM patients.

γ-Tocotrienol

γ-Tocotrienol is a member of the vitamin E superfamily derived from palm oil and rice bran. This agent has gained much attention in the last few years owing to its anti-proliferative and anti-carcinogenic potential [175177]. Our group demonstrated that γ-tocotrienol can suppress both constitutive and inducible STAT3 expression in HCC cells via inhibition of upstream kinases and induction of SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase 1) [178]. In a separate study, it was found that γ-tocotrienol also can significantly inhibit NF-κB activation in diverse tumour cell lines [177]. Collectively, these results again demonstrate the potential efficacy of γ-tocotrienol in clinical management of various important malignancies.

Ursolic acid

Ursolic acid is a pentacyclic triterpenoid that is commonly found in everyday foods such as loquat, rosemary, apples, cranberries, pears and prunes. Using various tumour cell lines and mouse models, our group demonstrated that ursolic acid possess the ability to inhibit NF-κB/STAT3 activation through diverse molecular mechanism(s) [179,180]. Overall, these findings indicate the tremendous potential of these natural anti-cancer/anti-inflammatory compounds in not only inhibiting tumour growth, but also reducing some of the debilitating side effects associated with administration of conventional chemotherapy to cancer patients.

CONCLUSIONS

There is definitely growing evidence to suggest that chronic inflammation is a critical mediator of tumorigenesis. Mediators of chronic inflammation inevitably contribute to tumour initiation and development, as well as progression. Up-regulation and overexpression of these molecular mediators often serve as a prognostic marker for cancer patients. For instance, as discussed above, increased levels of CXC chemokines are not only associated with chemoresistance, but also may contribute to poor prognosis in patients. With an increase in scientific reports related to the close association between chronic inflammation and cancer, the spotlight has been shifted on to identification of pharmacological blockers that may have the potential to significantly down-modulate these pro-inflammatory mediators. However, caution must be practised before exerting a claim that all inflammatory processes may always lead to pathogenic consequences. For instance, there are few drugs that can suppress inflammatory pathways, but with tumorigenic, rather than tumoristatic, results. For example, He et al. [181] reported that inhibition of NF-κB activation via IKKβ deletion resulted in acceleration of HCC development. Moreover, administration of TNFα blockers has been associated with increased risk of lymphoma development [182]. Taken collectively, targeted inhibition of pro-inflammatory pathways can be regarded as a double-edged sword, and a fine balance needs to be maintained to obtain optimum therapeutic benefits.

Naturally derived therapeutic agents hold significant promise for cancer therapy as they exhibit both chemopreventive and chemotherapeutic effects. Compared with synthetic compounds, drugs derived from natural sources exhibit comparatively fewer adverse effects and may potentially be more cost-effective. However, therapeutic application of natural compounds in patients is greatly hampered owing to a lack of availability of reliable clinical trials. Hence well-designed clinical studies are required before these natural agents can be tested in cancer patients. Finally, we also have to understand the limitations of cancer treatment, in that not every recipient may respond to a given drug in an identical fashion. Hence there is also a recent shift of focus towards personalized medicine, where the patient genomic profile is assessed before administration of a treatment regimen in order to optimize the therapeutic outcome [183185]. Despite a surge of reports highlighting the feasibility and efficacy of personalized medicine, conventional core cancer therapeutics still need to be utilized efficiently. Overall, coupling of high-throughput genomic technologies with existing conventional cancer therapeutics may lead to desirable clinical outcomes in cancer patients in the near future.

FUNDING

This work was supported by a National University Health System (NUHS) Bench-to-Bedside-To-Product grant to G.S.

Abbreviations

     
  • CCL

    CC chemokine ligand

  •  
  • COX

    cyclo-oxgenase

  •  
  • CSC

    cancer stem cell

  •  
  • CXCL

    CXC chemokine ligand

  •  
  • CXCR

    CXC chemokine receptor

  •  
  • EGF

    epidermal growth factor

  •  
  • EMT

    epithelial–mesenchymal transition

  •  
  • FDA

    Food and Drug Administration

  •  
  • gp130

    glycoprotein 130

  •  
  • HCC

    hepatocellular carcinoma

  •  
  • HGF

    hepatocyte growth factor

  •  
  • HIF-1

    hypoxia-inducible factor-1

  •  
  • IFNγ

    interferon γ

  •  
  • IκB

    inhibitor of NF-κB

  •  
  • IKK

    IκB kinase

  •  
  • IL

    interleukin

  •  
  • IL-6R

    IL-6 receptor

  •  
  • JAK

    Janus kinase

  •  
  • LIF

    leukaemia-inhibitory factor

  •  
  • MDSC

    myeloid-derived suppressor cell

  •  
  • MM

    multiple myeloma

  •  
  • MMP

    matrix metalloproteinase

  •  
  • NF-κB

    nuclear factor κB

  •  
  • PGE2

    prostaglandin E2

  •  
  • RA

    rheumatoid arthritis

  •  
  • RNS

    reactive nitrogen species

  •  
  • ROS

    reactive oxygen species

  •  
  • SOCS3

    suppressor of cytokine signalling 3

  •  
  • STAT

    signal transducer and activator of transcription

  •  
  • TAM

    tumour-associated macrophage

  •  
  • TAN

    tumour-associated neutrophil

  •  
  • TERT

    telomerase reverse transcriptase

  •  
  • TGFβ

    transforming growth factor β

  •  
  • TLR

    Toll-like receptor

  •  
  • TNFα

    tumour necrosis factor α

  •  
  • TNFi

    TNFα inhibitor(s)

  •  
  • TxA2

    thromboxane A2

  •  
  • VEGF

    vascular endothelial growth factor

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