Review

Inflammation and cancer: Till death tears them apartT.P. Raposo a,b, B.C.B. Beirão a, L.Y. Pang a, F.L. Queiroga b, D.J. Argyle a,*a The Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, United Kingdomb Center for Research and Technology of Agro-Environment and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal

A R T I C L E I N F O

Article history:Accepted 11 April 2015

Keywords:Veterinary oncologyCancerInflammationMacrophagesStem cellsMetastasis

A B S T R A C T

Advances in biotechnology have enabled the collection of an immeasurable amount of information fromgenomic, transcriptomic, metabolomic and proteomic studies of tumours within their microenviron-ments. The dissection of cytokine and chemokine networks has provided new clues to the interactionsbetween cancer cells and their surrounding inflammatory landscape. To bridge the gap between chronicinflammation and cancer, dynamic participants in the tumour microenvironment have been identified,including tumour-associated macrophages (TAMs) and regulatory T cells (Tregs). Both of these cell typesare notable for their ability to cause immunosuppressive conditions and support the evasion of tumourimmune surveillance. It is clear now that the tumour-promoting inflammatory environment has to beincluded as one of the major cancer hallmarks. This review explores the recent advances in the under-standing of cancer-related inflammation and how this is being applied to comparative oncology studiesin humans and domestic species, such as the dog.

© 2015 Elsevier Ltd. All rights reserved.

Introduction

The link between cancer and inflammation is not new, havingbeen first postulated by Virchow in 1863, and then revived morerecently by Frances Balkwill and Alberto Mantovani (2001). Theseauthors observed many similarities in the microenvironment ofchronic inflammatory conditions and tumours, suggesting a role forinflammatory cells and cytokines in tumour progression and im-munosuppression. Moreover, while accepting the hypothesis ofcancer as a clonal disease (Boveri, 2008), they proposed that in-flammatory conditions would act as a propellant for genetic changes.

When Hanahan and Weinberg (2000) described the features ofmost cancer types, the inflammatory microenvironment was not in-cluded in the famous six cancer hallmarks. Cancer-relatedinflammation was proposed as a seventh cancer hallmark by Colottaet al. (2009) in the face of extensive evidence relating to genetic in-stability caused by inflammation (e.g. downregulation of DNA repairpathways and induction of microsatellite instability), ultimately con-tributing to the genetic heterogeneity of tumours. A decade later,Hanahan and Weinberg (2011) revised their list of cancer hall-marks, this time highlighting the importance of tumour-promotinginflammation in the acquisition of core cancer hallmarks.

The origins and types of inflammation in cancer

Inflammation can play a key role in cancer, from initiation of themalignant phenotype to metastatic spread (Fig. 1). This review will

focus on the cellular and chemical mediators of inflammation thatsupport cancer progression. At this juncture it is worth consider-ing the origins of inflammation in cancer and how these contributeto carcinogenesis, cancer invasion and metastasis to distant sites(Fig. 2).

Inflammation arising from infection, autoimmunity or theenvironment

There are several examples of inflammation contributing to theinitiation of cancer, including: (1) infectious agents directly causingcancer, e.g. feline leukaemia virus (FeLV; Beatty, 2014), or promot-ing inflammation, e.g. Helicobacter pylori causing mucosa-associatedlymphoid tissue (MALT) lymphoma or gastric carcinoma in humans(De Falco et al., 2015); (2) immune-mediated disease promotingchronic inflammation, e.g. inflammatory bowel disease (IBD) andcolon cancer (Francescone et al., 2015); (3) subclinical inflamma-tion, e.g. obesity causing inflammation and predisposing to livercancer (Calle and Kaaks, 2004); (4) environmental carcinogens, e.g.smoke pollution (Cohen and Pope, 1995).

Although there are several mechanisms by which inflamma-tion may initiate cancer, it usually requires a switch from acute tochronic inflammation (Coussens and Werb, 2002) (Fig. 3). Inflam-matory cells produce reactive oxygen species (ROS) and reactivenitrogen intermediates (RNI), which enhance the mutation rate ofcells, induce DNA damage and increase genomic instability (Warisand Ahsan, 2006). These molecules also inactivate mismatch repairfunctions, supporting tumour initiation. In a positive feedback loop,DNA damage can also lead to inflammation, supporting tumour pro-gression (Ohnishi et al., 2013).

* Corresponding author. Tel.: +44 131 6506241.E-mail address: david.argyle@ed.ac.uk (D.J. Argyle).

http://dx.doi.org/10.1016/j.tvjl.2015.04.0151090-0233/© 2015 Elsevier Ltd. All rights reserved.

The Veterinary Journal ■■ (2015) ■■–■■

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

Contents lists available at ScienceDirect

The Veterinary Journal

journal homepage: www.elsevier.com/ locate / tv j l

Inflammation arising from tumours

Once a tumour is established, the microenvironment rein-forces a chronic inflammatory environment (Hanahan and Weinberg,2011). Tumours trigger an intrinsic inflammatory response and apro-tumourigenic microenvironment, supported by macrophage in-filtration and orchestrated by chemical mediators, such as interleukin(IL)-8 and IL-10. The cellular infiltrates, cytokines and chemokines:

(1) are pro-angiogenic and support angiogenesis in cancer; (2) actas growth factors for tumour cells; (3) promote epithelial-to-mesenchymal transition (EMT).

Inflammation arising from cancer therapy

Paradoxically, conventional cancer treatments (chemotherapy andradiotherapy) may support tumour growth through enhancing

Fig. 1. Inflammation plays a key role in cancer from initiation, propagation and, ultimately, metastatic disease.

Fig. 2. Cancer related inflammation can arise: (1) extrinsically from an infectious or environmental factor; (2) from the tumour (which is pro-inflammatory), or (3) fromthe effects of cancer therapy (radiation and chemotherapy).

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

2 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

inflammation. Chemotherapy and radiation induce an inflamma-tory response that may promote tumour growth or enhance anti-tumour immunity, but the mechanisms that determine the outcomeare poorly understood. Chemotherapy and radiation kill cells, whichcan lead to necrosis, which is pro-inflammatory (Vakkila and Lotze,2004). In response, danger-associated molecular patterns (DAMPS),e.g. heat shock protein 90 (HSP90), are released, which can promoteregrowth of cancer cells and also stimulate anti-tumour immuni-ty. The final outcome is probably dependent on tumour type, tumourmicroenvironment and type of treatment.

The role of inflammation in tumour initiation andmaintenance

Inflammation and cancer are closely linked (Table 1). Underly-ing infections are responsible for approximately 25% of deaths bycancer in Sub-Saharan Africa and Eastern Asia (Soerjomataram et al.,2012), supporting the role of chronic inflammation as a cofactor forcarcinogenesis. Causes of chronic inflammation, such as infectiousagents, immune-mediated disease and allergies, can create an en-vironment for initiation of cancer. Although inflammation has beenconsidered to be important in anti-tumour responses, recent evi-dence suggests that tumour associated inflammation may actuallyhave a tumour promoting effect. Inflammatory cells and media-tors may support the cancer development (1) by providing amicroenvironment that supports tumour initiation, cellular prolif-eration and local invasion; this includes the production of ROS andRNI, which are mutagenic; (2) by providing an environment thatsupports neo-angiogenesis, and (3) as inflammatory cells and as-sociated cytokines can support metastatic spread through theinduction of EMT (Grivennikov et al., 2010).

The observation that tumours harbour inflammation similar tonon-neoplastic tissues after an insult supports the concept thattumours are ‘wounds that never heal’ (Dvorak, 1986). Infiltrationof macrophages and lymphocytes is often associated with tumour

progression, increased angiogenesis, metastatic spread and a worseprognosis in several cancer types in humans and dogs. Long-termor metronomic use of non-steroidal inflammatory drugs (NSAIDs)has preventive, palliative and therapeutic value in cancer types pre-senting with tumour promoting inflammation (Table 2).

Inflammation and cancer share intrinsic and extrinsic pathways;in the intrinsic pathway, activation of oncogenes regulates theinflammatory microenvironment; in the extrinsic pathway, theinflammatory microenvironment conditions support cancerdevelopment. These two pathways are brought together bytranscription factors (e.g. nuclear factor κ light chain enhancer ofactivated B cells, NF-κB), cytokines (e.g. tumour necrosis factor-α,TNF- α) and chemokines (e.g. IL-8), which recruit leucocytes to thetumour microenvironment (Mantovani et al., 2008). In addition, theinflammatory conditions are modulated by tumour products;immunosuppressive cytokines allow immune evasion and recruittumour-promoting inflammatory cells, such as myeloid-derivedsuppressor cells, regulatory T cells, and tumour promoting(M2) macrophages (Balkwill et al., 2005) (Fig. 4). The tumourmicroenvironment represents a complex network of influences fromtumour cells, supporting stroma and inflammatory cells, whichcooperate to support the malignant phenotype (Fig. 5).

Bridging cancer and inflammation

Following exposure to pathogens, innate and specific immuneresponses may cooperate during acute inflammation to eliminatethe cause of infection and prevent further tissue damage. However,when the condition causing the initial inflammation is not re-solved, a long term chronic inflammatory state may be established(Fig. 5). This leads to a persistent immune cell infiltrate coupled withthe release of ROS, reactive nitrogen species (RNS) and macro-phage migration inhibitory factor (MIF), which can lead to DNAdamage. Such an environment is similar to that required for cancerinitiation and propagation (Kipanyula et al., 2013). The transition

Fig. 3. An inciting effect initially can cause an acute inflammatory environment. Failure of this acute inflammation to resolve can lead to chronic inflammation mediated byinflammatory cells (e.g. macrophages), cytokines and chemokines. Production of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) can cause tumourinitiation through the effects on DNA. Continued inflammation enhances tumour propagation and metastasis.

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

3T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

from chronic inflammation to cancer can be mediated by a numberof versatile molecules that are involved in both inflammation andcancer; these include NF-κB and IL-6.

Central role of NF-κB

NF-κB plays a key role in regulating the immune response to in-fection and dysregulation has been linked to conditions such asautoimmunity and cancer. The key role that this molecule plays incancer can be summarised as follows: (1) constitutive NF-κB ex-pression has been identified in many cancer types, supporting itsrole in promoting the cancer phenotype (Chaturvedi et al., 2011);(2) dysregulation of the NF-κB pathway has been documented

extensively in haematological malignancies and lymphoma; theselymphoid malignancies feature aberrant NF-κB activation, which pro-motes tumourigenic cell survival, protects against apoptosis andfavours oncogenesis (Karin, 2006; Escárcega et al., 2007); (3) con-stitutive activation of NF-κB is a hallmark of chronic inflammatorydisease, the latter also being associated with an increased inci-dence of cancer (Karin, 2008); (4) in human non-Hodgkin’slymphoma (NHL), the main mechanisms of dysregulation of the NF-κB signalling pathway include chromosomal mutations and viralprotein stimulation (e.g. Epstein Barr virus, human T-cell leukae-mia virus-1, HTLV-1) (Hiscott et al., 2001); (5) up-regulation of theanti-apoptotic Bcl-2 family proteins as a result of persistent acti-vation of the NF-κB pathway, with subsequent dysregulation of

Table 1Evidence for cancer-related inflammation.

Human medicine Veterinary medicine

S100A6, S100A8, S100A9 and S100A11are all expressed in common cancers,especially breast cancer; S100A11may have a direct influence on theproliferation of cancer cells (Crosset al., 2005).

Acute phase serum amyloid proteins areeffectors for the metastasis-promotingfunctions of S100A4 and serve as alink between inflammation andtumour progression (Hansen et al.,2014).

Acute phase protein profiles arealtered in mast cell tumours andsarcomas (Chase et al., 2012)Calgranulins S100A8/A9 andS100A12, proposed as biomarkersfor inflammatory diseases, areelevated in dogs with transitionalcell carcinoma or prostatecarcinoma versus dogs diagnosedwith a urinary tract infection(Heilmann et al., 2014).

Interferon (IFN)-γ enhances HOS andU2OS cell line susceptibility to γδ Tcell-mediated killing through theFas/Fas ligand pathway (Li et al.,2011).

Intra-tumoural adjuvant-Fas ligandcan induce a potent inflammatoryresponse, restoring local tumourimmune surveillance; dogs withhigher and inflammation andapoptosis scores had longersurvival times (Modiano et al.,2012).

Tumour-associated macrophages(TAMs) have a role in every step ofbreast cancer progression (Obeidet al., 2013).

TAMs are associated withhistological malignancy and haveprognostic value in caninemammary tumours (Krol et al.,2011b; Raposo et al., 2014).

Tumour-infiltrating lymphocytes (TILs)have prognostic value in patients withearly breast cancer; TILs can alsopredict outcome of neoadjuvantchemotherapy and are promisingbiomarkers of immune responses totumours (Melichar et al., 2014).

TILs have prognostic value incanine mammary tumours and areassociated with clinicopathologicalfeatures of malignancy(Estrela-Lima et al., 2010; Kimet al., 2010; Carvalho et al., 2011).

Myeloid-derived precursor cells(MDSCs) inhibit the host immuneresponse in human breast cancerpatients; inhibiting MDSCs mayimprove therapeutic outcomes(Markowitz et al., 2013).

MDSCs, p-STAT 3 and regulatory Tlymphocytes (Tregs) have a role inthe development ofimmunosuppression in dogs withskin and mammary cancer (Krolet al., 2011a).

The promotion of breast cancermetastasis in humans caused byinhibition of colony stimulating factor(CSF)-1 receptor (CSF-1R/CSF-1signalling is blocked by targeting thegranulocyte-CSF receptor (Swierczaket al., 2014).

CSF-1R acts as an inhibitor ofapoptosis and promoter ofproliferation, migration andinvasion of canine mammarycancer cells (Krol et al., 2013).

Colorectal cancer andcholangiocarcinoma are attributableto chronic inflammatory disease(Landskron et al., 2014).

The aetiology and pathogenesis ofgastric polyps in dogs remainsundefined, although severe chronicantral gastritis may predispose togastric polyps (Taulescu et al.,2014).

Cyclo oxygenase (COX)-2 has a role inthe metastasis of osteosarcoma byincreasing cell invasion andextracellular matrix degradation (Wuet al., 2014)

Global gene expression analysis ofcanine osteosarcoma stem cellsreveals a novel role for COX-2 intumour initiation and tumoursphere formation (Pang et al., 2014)

Table 2Use of non-steroidal anti-inflammatory drugs in cancer prevention or therapeutics.

Tumourlocalisation

Human medicine Veterinary medicine

Urinarytract

Clinical andimmunomodulatory effects ofcelecoxib plus interferon-alphain metastatic renal cellcarcinoma patients with COX-2tumour immunostaining(Schwandt et al., 2011)

Mitoxantrone + piroxicaminduced remission of a caninemodel of invasive humantransitional cell carcinoma(TCC) (Henry et al., 2003).Gemcitabine + piroxicamprovides an alternativetreatment for TCC with fewerside effects (Marconato et al.,2011).Retrospective evaluation ofdoxurubicin-piroxicamcombination treatment indogs with TCC (Robat et al.,2013)

Prostatic Effect of aspirin and othernon-steroidal anti-inflammatory drugs onprostate cancer incidence andmortality: a systematic reviewand meta-analysis (Liu et al.,2014)

Evaluation of COX-1 andCOX-2 expression and theeffect of COX inhibitors incanine prostatic carcinoma(Sorenmo et al., 2004)

Colorectal Celecoxib therapy inconjunction withchemoradiation was notassociated with additionaltoxicity and seemed to helpmitigate therapy-related pain(Debucquoy et al., 2009)

CD4+ T cell cytokine gene andprotein expression induodenal mucosa of dogswith inflammatory bowelIL-10 might have a role in thepathogenesis of inflammatorycolorectal polyps (Ohta et al.,2014).

Mammary The combination ofcapecitabine and celecoxib isactive and safe in far advancedmetastatic breast cancerpatients and results in a lowertoxicity than single-agentcapecitabine (Fabi et al., 2008).

Usefulness of selective COX-2inhibitors as therapeuticagents against caninemammary tumours (Saitoet al., 2014)

Skin Celecoxib may be effective forprevention of squamous cellcarcinomas (SCCs) and basalcell carcinomas (BCCs) inindividuals who have extensiveactinic damage and are at highrisk for development of non-melanoma skin cancers(Elmets et al., 2010).Complete and long-lastingregression of disseminatedmultiple skin melanomametastases under treatmentwith COX-2 inhibitor (Lejeuneet al., 2006)

Piroxicam may be used for thetreatment of oral SCCs(Schmidt et al., 2001).Cisplatin administered incombination with piroxicamhad antitumour activityagainst oral melanoma andSCC, presenting acceptablelevels of toxicity (Boria et al.,2004)

Brain Radiotherapy plus celecoxib issafe and a possible activetreatment for patients withbrain metastasis (Cerchiettiet al., 2005).

Mavacoxib inhibits cellproliferation of a canineglioma cancer cell line (Panget al., 2014).

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

4 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

apoptosis, has been established as a major cause of resistance tochemotherapy and is associated with an aggressive clinical courseand a poor survival for various haematopoietic malignancies (Brienet al., 2007); (6) a significant impediment to current cancer treat-ment regimens is the acquisition of resistance to the cytotoxic effects

of chemotherapeutic agents. Ironically, many chemotherapeuticagents that trigger p53-mediated apoptosis also activate NF-κB (Dasand White, 1997).

In various in vivo and in vitro models, NF-κB inhibition in-creases the efficacy of anticancer agents and reduces the incidence

Fig. 4. Macrophages have either an acute inflammation-associated (M1) or tumour promoting (M2) phenotype; this probably reflects two ends of a phenotypic spectrum.

Fig. 5. Summary of the cells and mediators within the tumour microenvironment, demonstrating the diversity of inflammatory and stromal cells interacting with cancercells, and their role in tumour progression, angiogenesis and metastasis.

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

5T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

of resistance to these agents, making NF-κB a potential drug targetin oncology (Nakanishi and Toi, 2005). However, the NF-κB pathwayis involved in complex cross-talking with many cancer-related sig-nalling pathways (protein kinases, c-Jun N-terminal kinase, STAT3,and transcription factors, such as p53) and concern has been raisedover the potential use of NF-κB inhibitors for cancer therapeuticsbecause of unpredictable secondary effects (Hoesel and Schmid,2013).

Mudaliar et al. (2013) recently analysed gene expression pro-files of diffuse large B cell lymphoma (DLBCL) in humans and dogs.Among the signalling pathways shared between human and canineDLBCL, the NF-κB, PI3K/AKT, Notch and JAK/STAT pathways wereenriched. Moreover, there was upregulation of IL-10, IL-6 and IL-2, which further supports the hypothesis of shared links betweencancer and inflammation, mediated by NF-κB, cytokine andchemokine signalling.

The role of NF-κB signalling has been explored extensively inhuman breast cancer (Ling and Kumar, 2012; Brown, 2013; Zubairand Frieri, 2013), as well as canine mammary tumours (Vinothiniet al., 2009; Mkaouar et al., 2011, 2012). In dogs, nuclear NF-κB ex-pression is correlated with larger tumour size, lymph nodemetastasis, higher mitotic index and shorter survival (Mkaouar et al.,2012). Using canine mammary tumour cell lines in a mouse xeno-graft experimental model, reductions in tumour growth andmetastasis followed NF-κB inhibition (Mkaouar et al., 2011).

Role of interleukin-6 in mediating cancer-related inflammation

IL-6 is implicated as a key cytokine linking inflammation withcarcinogenesis. Overexpressed across several cancer types(Zarogoulidis et al., 2013), IL-6 is highlighted as a multifunctionalkey player in pro-inflammatory conditioning of carcinogenesis. IL-6-mediated STAT3/NF-κB signalling is induced by simultaneous p53and phosphatase and tensin homologue (PTEN) knockdown in amodel of triple negative breast cancer. These mutations also leadto EMT changes in cancer stem cells (CSCs), which could be re-versed by ectopic expression of SOCS3, a negative regulator of theIL-6 pathway (Kim et al., 2014a). Increased IL-6 protein accompa-nies progression in canine mammary tumours (Kim et al., 2010),similar to the role of systemic IL-6 in the progression of human breastcancer (Dethlefsen et al., 2013). IL-6 also acts as a modulator of theimmune system, particularly of maturation of dendritic cells (DCs)and other antigen-presenting cells (APCs). IL-6 signalling can bepolarised towards anti- or pro-inflammatory functions, with the ac-tivation of JAK1-STAT3, RAS-MAPK and PI3K-AKT (Yao et al., 2014).

The role of IL-6 in DC maturation in the tumour microenviron-ment has been investigated in canine transmissible venereal tumour(CTVT) (Lin et al., 2013). After inhibition of monocyte-derived DCsby tumour-derived transforming growth factor (TGF)-β, IL-6 treat-ment blocked the TGF-β/Smad7 axis and restored DC function. Duringthe regression phase of CTVT, host-derived IL-6 and interferon (IFN)-γpromoted expression of major histocompatibility complex (MHC)antigens (Hsiao et al., 2008). This might seem contradictory, sinceconstitutive IL-6 activation is tumour promoting (Kim et al., 2014a).However the different signalling pathways and effects of IL-6 mighthelp explain this discrepancy.

Zhong et al. (2014) demonstrated that, within the tumour mi-croenvironment, DCs can be transformed to regulatory DCs (DCregs)with an immunosuppressive and pro-tumourigenic phenotype. Thistransformation is mediated by small Rho GTPases and STAT3, whichare involved in IL-6 signalling (Zhong et al., 2014). IL-6 promotesdifferentiation of T helper (Th)17 cells in conjunction with TGF-β(Veldhoen et al., 2006); Th17 cells play a role in inflammation andtissue injury, and are also found frequently in pre-malignant andmalignant lesions (Muranski and Restifo, 2013).

IL-6 can act as a ‘friend’ or ‘foe’ at the interface between cancerand inflammation, and can interact with NF-κB in an amplifying loopof inflammation that promotes carcinogenesis. Simultaneous acti-vation of NF-κB and STAT3 in non-immune cells occurs in the tumourmicroenvironment and upregulates IL-6 expression (Atsumi et al.,2014), acting as an ‘inflammation amplifier’ (Fig. 3). This mecha-nism appears to be responsible for the transition between acute andchronic inflammation, perpetuating genetic instability and increas-ing the diversity of mutations in the cancer cell genome (Atsumiet al., 2014).

Within the tumour microenvironment, diverse cytokines andchemokines mediate paracrine and autocrine signalling among dif-ferent cell types, including TAMs, fibroblasts, regulatory T cells andcancer cells (Table 3). TAMs are key orchestrators of the tumourmicroenvironment, directly affecting neoplastic cell growth, angio-genesis and extracellular matrix (ECM) remodelling (Solinas et al.,2009).

A leading cellular role in cancer: Tumour-associatedmacrophages

Solid tumours contain a significant population of infiltratingmyeloid cells (Solinas et al., 2009). Migration of leucocytes intotumours was first interpreted as evidence of an immunological re-sponse of the host against the tumour. However, some tumours arenon-immunogenic; infiltrating leucocytes in these tumours supportneoplastic progression by promoting angiogenesis, inducing tissueremodelling through matrix metalloproteinases (MMPs) and sup-pressing anti-tumour immune responses (Sica et al., 2006; Zeisbergeret al., 2006).

Monocyte (macrophage) infiltration occurs throughout the de-velopment of a tumour, from early nodules to late stage metastaticcancers (Ohno et al., 2004; Lewis and Pollard, 2006). The produc-tion of pro-inflammatory factors (e.g. cytokines and prostaglandins)associated with tumour growth creates a microenvironment re-sponsible for recruiting and activating leucocytes. These leucocytesare derived largely from blood monocytes and are recruited to thetumour site by mediators such as chemokine (C-C motif) ligand 2(CCL2)/monocyte chemotactic protein 1 (MCP-1), CCL3-5, CCL8, vas-cular endothelial growth factor (VEGF) and colony stimulatingfactor-1 (CSF-1) (Zeisberger et al., 2006). These leucocytes promoteangiogenesis (dependent or independent of VEGF expression). Otherpro-angiogenic factors involved in this process are angiopoietins(Ang1 and Ang2), CCL2, thymidine phosphorylase, CXCL8 andcyclooxygenase-2 (COX-2) (Polverini and Leibovich, 1984; Lewis andPollard, 2006).

The formation of a high density vessel network is associated withprogression to malignancy, whereas primary tumour infiltrating mac-rophages can regulate both vessel formation and tumour progression.Tumour size is not necessarily a determinant of the formation ofnew blood vessels and malignancy, whereas the presence of mac-rophages is an important determinant. Mice that are null for themononuclear phagocytic receptor CSF-1R (op/op) have 60% reducedfrequency of malignant transformation compared to normal mice,suggesting a role for CSF-1 signalling in this process (Lin et al., 2006).

Signalling of CSF-1 through its receptor CSF-1R is a critical reg-ulator of survival, differentiation and proliferation of macrophages,and is considered to be a key mediator of TAM infiltration(Aharinejad et al., 2004; Lin et al., 2006; Sica et al., 2006; Wyckoffet al., 2007; Mantovani et al., 2008; Hagemann et al., 2009; Robinsonet al., 2009). Cancer cells, as well as tumour macrophages, can expressCSF-1 and its receptor (Sica et al., 2006).

TAMs may also contribute to tumour cell proliferation throughthe production of epidermal growth factor (EGF), platelet derivedgrowth factor (PDGF), TGF-β1, hepatocyte growth factor (HGF) andbasic fibroblast growth factor (bFGF) (Lewis and Pollard, 2006).

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

6 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

Autocrine and paracrine signalling through CSF-1R and the pres-ence of macrophages support invasion and the metastatic phenotype(Aharinejad et al., 2004; Wyckoff et al., 2007; Joyce and Pollard, 2009;Patsialou et al., 2009). Perivascular macrophages play a major role

in the intravasation of cancer cells. Cancer cells are able to migratetowards perivascular macrophages, which are located at sites of in-travasation and promote this event (Wyckoff et al., 2007).Macrophages (CD11b+) are also capable of lymphangiogenesis,

Table 3Key players in the tumour microenvironment and their main effects.

Effects on tumour microenvironment

CytokinesCSF-1 Colony stimulating factor-1 Attraction of macrophages; induction of CSF-1/epidermal growth factor

(EGF) metastatic loop (Patsialou et al., 2009)IFN-γ Interferon gamma Anti-tumour mechanisms in cell mediated responses/potential immune

suppression in some conditions (Zaidi and Merlino, 2011)IL-1 Interleukin-1β Increase in chemokine production (Talmadge et al., 2007)IL-10 Interleukin-10 Anti-inflammatory effects; immunosuppression; modulation of expression

of chemokine receptors (Kamradt, 2012)IL-2 Interleukin-2 Tumour mitogen (Talmadge et al., 2007)IL-6 Interleukin-6 Tumour growth factor; inflammation amplifier (Atsumi et al., 2014)IL-8/CXCL8 Interleukin-8 Angiogenesis and osteolysis; promotion of migration and invasion of

tumour cells (Waugh and Wilson, 2008)TNFα Tumour-necrosis alpha Induction of matrix metalloproteinases (MMPs), vascular endothelial

growth factor (VEGF), nitric oxide synthase (NOS)-2 and cyclo-oxygenase(COX)-2; enhancement of angiogenesis (Talmadge et al., 2007)

Growth factors and hormonesEGF Epidermal growth factor Activation of MMPs; VEGF expression; autocrine growth and angiogenesis

(Patsialou et al., 2009)HGF Hepatocyte growth factor Production of chemokines and mitogens; angiogenesis (Lewis and Pollard,

2006)PGE2 Prostaglandin E2 Activation of epidermal growth factor receptor (EGFR); increase in motility

and changes in cell morphology; induction of myeloid-derived suppressorcells (MDSCs) (Sheng et al., 2001; Pai et al., 2002; Sinha et al., 2007)

TGFβ1 Transforming growth factor β1 Epithelial to mesenchymal transition (EMT) (Cervantes-Arias et al., 2013)VEGF Vascular endothelial growth factor Intra-tumoural angiogenesis; growth factor for endothelial cells;

chemoattraction of monocytes; inhibition of apoptosis (Zeisberger et al.,2006)

AKT or PKB Protein kinase B Mutations lead to cell proliferation and anti-apoptosis effects (Osaki et al.,2004)

ChemokinesCCL2/MCP-1 Monocyte chemotactic protein-1 Attraction of macrophages; homing of metastasis; permeability of

vascular endothelial cells (Zhang et al., 2010)CCL3/MIP-1α Macrophage inflammatory protein-1α Activates C-C chemokine receptor type 1 (CCR1), inducing metastasis,

angiogenesis and tumour infiltration of Küpffer cells (Koizumi et al., 2007)CCL4/MIP-1β Macrophage inflammatory protein-1β Induces MMP9 in macrophages (Balkwill, 2004)CCL5 or RANTES Regulated upon activation, normally T-expressed Proliferation and invasiveness (Balkwill, 2004)CCL8 or MCP-2 Monocyte chemotactic protein 2 Anti-tumour effects; recruitment of monocytes to the tumour (Balkwill,

2004; Sica et al., 2006)Enzymes and protein regulators

COX-2 Cyclooxygenase 2 Tumour growth and proliferation; VEGF-induced angiogenesis; inhibitionof apoptosis (Thun et al., 2002)

JAK-1 Janus kinase 1 Inhibition of apoptosis; induction of cell proliferation; promotion oftumour invasion (Xiong et al., 2008)

LPS Lipopolysaccharide LPS induces cell adhesion and invasiveness and cytotoxic macrophages(Hsu et al., 2011)

MAPK Mitogen activated protein kinase Cell proliferation; signal transduction for many factor receptors, such asEGFR (Fang and Richardson, 2005)

MIF Macrophage inhibitory factor Inflammatory activation of macrophages; induces tumour suppression(Mitchell and Bucala, 2000)

MMP-2 Metalloproteinase 2 Proteolysis of extracellular matrix; invasion and metastasis (Talmadgeet al., 2007)

MMP-9 Metalloproteinase 9 Proteolysis of the extracellular matrix; tissue remodelling (Talmadge et al.,2007)

NF-κB Nuclear factor κB Multifunctional transcription factor (Ben-Neriah and Karin, 2011)NOS Nitric oxide synthases Induction of NO-mediated p53 mutation (Kipanyula et al., 2013)Notch Notched wing genes of mutant Drosophila melanogaster Mutation induced proliferation/potential tumour suppression; effect is

context dependent (Allenspach et al., 2002)p53 p53 Mutation stops cell cycle arrest and apoptosis (Munro et al., 2005)PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase Mediation of survival signals through several receptors (Carnero et al.,

2008)PTEN Phosphatase and tensin homologue Tumour suppressor gene; mutation induces cell survival and increased

size of tumour (Keniry and Parsons, 2008)RAS Protein superfamily of small GTPases Regulates pathways important for cell survival and proliferation (Prior

et al., 2012)ROS Reactive oxygen species Reaction to stressors affecting inflammation; cell transformation (Gupta

et al., 2012)SOCS3 Suppressor of cytokine signalling 3 i Modification of macrophage activation; affects inflammation through

STAT3 (Hiwatashi et al., 2011)STAT3 Signal transducer and activator of transcription 3 Transcription factor signalling; affects myeloid cell response to tumours

(Hiwatashi et al., 2011)uPA Urinary plasminogen activator Cell migration and invasion (Wolff et al., 2011)

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

7T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

normally induced by VEGF and IL-1β, by forming tubular struc-tures that express several markers of lymphatic endothelium andso provide other means for the dissemination of cancer cells(Maruyama et al., 2005).

Metastasis through normal tissue invasion may be facilitated bythe presence of TAMs and stimulation by CSFs. These factors are ableto induce higher expression of MMP-2 and MMP-9, as well as uro-kinase plasminogen activator (uPA), which generates plasmin, anextracellular protease (Pei et al., 1999; Lewis and Pollard, 2006).

Krol et al. (2011b) observed CSF-1R expression in both mac-rophages and neoplastic cells in canine mammary tumours. Asignificant increase in CSF-1R expression was observed in caninemammary adenocarcinomas with a higher histological grade of ma-lignancy and those that went on to metastasise; this could be relatedto an enhanced ability of CSF-1R-expressing tumour cells tometastasise (Krol et al., 2011b). CSF-1R also inhibited apoptosis, andpromoted proliferation, migration and invasion of canine mammarytumour cells (Krol et al., 2013).

The prognostic value of TAM infiltration has also been studiedin canine mammary tumours; malignancy and aggressive behaviourwas proportional to macrophage density and increased TAM infil-tration is linked to shorter survival times (Raposo et al., 2013).Increased infiltration by TAMs is also associated with increased VEGFexpression, but not with increased microvessel density, suggest-ing a role in angiogenesis, especially in hypoxic tumour areas (Raposoet al., 2014).

Tumour-associated macrophages and immunosuppression:M1 and M2 phenotypes

In addition to its direct effect on tumour promotion, CSF-1signalling and macrophage activity in tumours can have immuno-suppressive effects. ‘Weaker’ immune responses are believed to playa role in tumour development (Bronte et al., 2001). The classicmonocyte/macrophage response to CSF-1 signalling is activationtowards an inflammatory function, with enhanced cytokine secre-tion, bacterial killing and stimulation of Th2 responses (Chitu andStanley, 2006). Although CSF-1 can increase immune responsesagainst potential pathogens by stimulation of macrophages, it canalso reduce antigen specific and mitogen induced T cell prolifera-tion or macrophage stimulation of T cells (Bartocci et al., 1987; Sesteret al., 1999). Macrophages may have anti-tumour effects; however,to achieve this, cells must be appropriately stimulated to exhibitwhat has been termed the M1 classical phenotype (activated by mi-crobial products or IFN-γ). Despite this, a microenvironmentpromoting a M1 phenotype is not usually found within tumours (Sicaet al., 2006).

There is substantial evidence that most TAMs have a M2 phe-notype (Fig. 4). This phenotype is stimulated by signals originatingfrom regulatory T cells (Tregs) or from tumour cells, which secreteCSF-1 and other cytokines, leading to inhibition of the cytotoxic po-tential of TAMs (e.g. IL-10, IL-4, IL-6, MDF, TGF-β1, PGE2) (Lewis andPollard, 2006; Sica et al., 2006; Hagemann et al., 2009). The M2 typeof activation promotes angiogenesis, tissue remodelling and animmunosuppressive phenotype, all of which support tumour ma-lignancy (Sica et al., 2006). These macrophages exert a directcytotoxic and suppressor activity against T cells as a result of in-creased secretion of prostaglandin (PG) E2, nitric oxide (NO), H2O2,reactive oxygen intermediates and TNF-α. However, the M1 and M2phenotypes probably represent the extremes of a spectrum of phe-notypes very difficult to dissect in patient-derived material.

Chemotaxis and metastasis: CCL2/CCR2 axis

Monocyte chemotactic protein-1 (MCP-1 or CCL2) is one of thekey mediators of interactions between tumour cells and host

immune cells. CCL2 plays an important role in modulating thetumour microenvironment and promoting neoplastic progressionin several tumour types. CCL2 is responsible for the recruitment ofmost macrophages and some T cells to the sites of inflammationat the periphery of tumours; by mediating interactions betweennormal and malignant cells in the tumour microenvironment, CCL2plays a multi-faceted role in tumour progression. Increased CCL2levels have been reported in several types of cancer and are oftenrelated to an increased infiltration of TAMs (Zhang et al., 2010).

In human breast cancer, overexpression of CCL2 contributes totumour progression and is associated with a poorer prognosis andearlier relapse after treatment (Ueno et al., 2000; Fujimoto et al.,2009). Blocking CCL2 in breast cancer cells impedes metastaticseeding, underpinning the role of the CCL2/C-C chemokine recep-tor type 2 (CCR2) axis in promoting breast cancer metastasis.Breast cancer cells secreting CCL2 induce monocyte-derived CCR2+

stromal cells to assist colonisation in the lung and bone, thereforefacilitating metastasis (Lu and Kang, 2009). CCL2 expression isalso upregulated in poorly differentiated breast cancers and sup-ports the formation of tumour spheres in vitro, whereas loss ofCCL2 delays tumourigenesis in cancer stem cells (CSCs) (Tsuyadaet al., 2012).

Using a mouse model of breast cancer, in the absence of TGF-β(a molecule known to be involved in EMT), CCL2 secretion by fi-broblasts is increased, promoting mammary tumour progressionthrough the recruitment of TAMs (Hembruff et al., 2010). CCL2 ex-pression facilitates liver metastasis by promoting cell proliferationand survival at the primary tumour site (Hembruff et al., 2010).

In vivo mouse models of human prostate cancer metastasis havedemonstrated cooperation between tumour cell-derived CCL2 andhost-derived CCL2 in promoting tumour growth. In particular, host-derived CCL2 appears to be involved in the ability of prostate cancersto metastasise and successfully colonise distant sites (Loberg et al.,2007). Similarly, in a mouse model of breast cancer metastasis,monocytes recruited by CCL2 promoted metastatic seeding (Qianet al., 2011).

The CCL2/CCR2 axis appears to have a major role in metastasis,including the early stages of progression, homing of metastaticcells and the final stages of the establishment of new, distanttumours. In CCR2+ cancer cells, Smad3-dependent signalling throughMEK-p42/44MAPK regulates CCL2-induced cell motility and sur-vival, two important features of the metastatic process (Fang et al.,2012). Moreover, CCL2-induced vascular permeability and metas-tasis are dependent on JAK2-Stat5 and p38 mitogen-activated proteinkinase (MAPK) signalling (Wolf et al., 2012). Upregulated CCR2expression has been demonstrated in regions of increased vascu-lar permeability in tumour-bearing human lungs (Hiratsuka et al.,2013). Vascular endothelial cells expressing CCR2 facilitate themigration of either macrophages or cancer cells, suggesting thatCCR2+ cells are attracted to cancer cells and facilitate the forma-tion of metastases.

The process of metastasis involves a series of events until thefinal establishment in distant organs. These events comprise ad-herence to blood or lymph vessels, extravasation, survival,establishment of micrometastases and persistent growth intomacrometastases. Ultimately, the survival of a metastasis dependson the interactions between tumour cells and the host immunesystem, all happening in the tumour or metastatic microenviron-ment (Joyce and Pollard, 2009; Qian and Pollard, 2012). Qian et al.(2009) identified a new population of macrophages, designatedmetastasis-associated macrophages (MAMs), which are characterisedby increased CCR2 and VEGFR1 expression. In a mouse model ofmetastatic breast cancer, MAMs played a central role in cancer cellextravasation and metastasis formation (Qian et al., 2009).

Serum CCL2 concentrations were significantly higher in dogs withmulticentric lymphoma than healthy control animals (Perry et al.,

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

8 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

2011). Higher concentrations of CC:2 were associated with reduceddisease-free intervals (DFIs) in dogs treated with chemotherapy basedon cyclophosphamide, hydroxy doxorubicin, oncovin and predni-sone (CHOP) (Perry et al., 2011). Serum CCL2 concentrations havebeen used as a marker to screen for neoplastic disease in dogs(Ishioka et al., 2012). Bernese Mountain dogs with histiocytic sar-comas had elevated serum CCL2 concentrations compared tounaffected dogs of the same breed (Nikolic et al., 2013). These ob-servations suggest that the CCL2/CCR2 axis may be an importanttherapeutic target for preventing metastatic disease.

Initiation of metastasis with interleukin-8

IL-8, also known as CXCL8, is a pro-inflammatory and pro-angiogenic chemokine, responsible for neutrophil chemotaxis anddegranulation (Waugh and Wilson, 2008). IL-8 is secreted by cancercells, mesenchymal cells and macrophages, and plays a central rolein tumour immunology and intercellular communication (Singh et al.,2013b).

In dogs, IL-8 expression has been studied in haemangiosarcomas(Kim et al., 2014b), osteosarcomas (Paoloni et al., 2009) and mammarytumours (Zuccari et al., 2011; Gelaleti et al., 2012). In genome-wide expression profiles of haemangiosarcoma cell lines and tumours,an IL-8 gene signature was associated with a reactive tumour mi-croenvironment; IL-8 expression is affected by the inflammation statusof tumour cells (Kim et al., 2014b). Conversely, no differences betweenhigh and low levels of immunohistochemical expression of IL-8 werefound in terms of inflammatory cell infiltrates, haemorrhage andtumour necrosis or tumour-associated fibrosis (Kim et al., 2014b).IL-8 secreted by tumours may be able to modify the tumour mi-croenvironment without attracting blood-circulating neutrophils thatcould participate in an anti-tumour response.

IL-8 promotes osteoclastogenesis and bone resorption under phys-iological conditions. In human breast cancer patients, increasedserum concentrations of IL-8 can be used to predict early meta-static disease (Benoy et al., 2004). In dogs with mammary tumours,increased IL-8 concentrations were associated with a poorer prog-nosis (Gelaleti et al., 2012).

Links between IL-8 and inflammation have been further ex-plored in mouse models and mammary cancer cell lines. Singh et al.(2006) conducted mechanistic studies demonstrating that IL-8 ex-pression in breast cancer and involvement in metastasis can bemediated by COX-2. The poorly metastatic cell line MCF7 did notproduce detectable levels of IL-8 after COX-2 overexpression; thismay be relevant to the observation that metastasis of breast cancerto bone requires IL-8 (Singh et al., 2006). In a mouse model of breastcancer metastasis, IL-8 was induced after docetaxel treatment andincreased the CSC pool; conversely, blockade of IL-8 receptors(CXCR1/2) by repertaxin resulted in a reduction of systemic me-tastasis, supporting the role of IL-8 signalling in inducing metastasisof CSCs (Ginestier et al., 2010).

Another important mechanism for the interaction between cancercells and the immune system is the transfer of tumour microvesicles(TMV) containing chemokines and chemokine mRNA. TMVs con-taining mRNA for IL-8 and several other chemokines induced de novosynthesis in monocytes (Baj-Krzyworzeka et al., 2010, 2011). TMVsinduced angiogenesis, chemotaxis of leucocytes and engulfment byCD14+CD16− cells, followed by ROI and IL-10 production, similar tothe effect of cancer cells on monocytes (Baj-Krzyworzeka et al., 2010,2011).

An IL-8-dependent inflammatory feedback loop in human breastcancer was suggested by Singh et al. (2013b) as a cytokine signa-ture. IL-8 and CXCL1 upregulation can be induced by HER2overexpression (Vazquez-Martin et al., 2007); targeting IL-8 recep-tors increases the efficacy of HER2 inhibition (Singh et al., 2013a).

Escaping immune surveillance: IL-10 in perspective

Escape from immune surveillance is a central hallmark of cancer.The understanding of cancer-related inflammation and overcom-ing immune tolerance is one of the main aims of current cancertargeted therapies (Lane et al., 2014). T cell tolerance is facilitatedby the chronicity of antigen exposure, resulting in lack of effectorfunction (Li et al., 2014). An important event coupled with T-celltolerance is immunosuppression by Tregs. Tregs are capable of se-creting IL-10, which is a potent suppressor of macrophages and Tcell effector functions and thus central to the control of immuneresponses (Kamradt, 2012).

The immunosuppressive role of IL-10 has been well docu-mented. IL-10 inhibits NF-κB translocation to the nucleus and thusprevents the immediate-early pro-inflammatory response (Lentschet al., 1997), as well as abrogating antigen presentation (Hashimotoet al., 2001). However, some studies have shown contradictory effectsfor IL-10 in immune cells, with the re-establishment of IFN-γ-dependent tumour immune surveillance. Mumm et al. (2011)demonstrated that IL-10 deficient mice have an increased frequen-cy of tumours, possibly due to uncontrolled inflammation, whichpredisposes to carcinogenesis. Using a transgenic mouse modeloverexpressing IL-10, Mumm et al. (2011) observed increased in-filtration of cytotoxic T cells and Th1 cells, coupled with elevatedIFN-γ and MHC class I expression, which suggests re-establishmentof tumour immune surveillance. This knowledge was then appliedinto a new therapeutic strategy against cancer, using pegylated IL-10 (pegylation improves the circulatory half-life) as a therapeuticapproach to strengthen cancer immunity (Mumm and Oft, 2013),but further clinical investigation is still required.

Higher serum concentrations of IL-10 were detected in dogs withinflammatory canine mammary tumours than in dogs with othermalignant canine mammary tumours (de Andres et al., 2013). Ohtaet al. (2014) suggested that IL-10 might have a role in the forma-tion of inflammatory colorectal polyps in dogs, in which increasedIL-10 expression is accompanied by high IFN-γ levels (Ohta et al.,2014).

The origin of cancer stem cells in an inflammatory context

The mechanisms underlying tumour promotion by cancer-related inflammation are not yet fully understood, but both CSCsand inflammatory cells in the surrounding tissue appear to play acentral role (Balkwill et al., 2005). The ability of CSCs to evolve (i.e.to adapt to new, hostile microenvironments) can be influenced bystates of inflammation, with coexistent hypoxia. Using networkmodels at the system level, Csermely et al. (2014) observed that fluc-tuations of stress factors regulate changes from plastic (greaterproliferation, symmetric cell division) to rigid networks (quies-cent states, asymmetric cell division). This continuous change in thetumour microenvironment ultimately contributes to the genera-tion of hostile conditions where CSCs develop. This generates greater‘evolvability’ and provides a basis for CSC development (Csermelyet al., 2014). The same authors have gathered evidence on the ex-istence of two phases of malignant transformation, starting withplastic networks that gradually become more rigid throughout car-cinogenesis (Csermely et al., 2014).

The concept of CSC evolvability suggests that one of the mainreasons for cancer recurrence after treatment is the generation ofmore CSCs through the application of selective pressure by suddenchanges in the microenvironment after radiation or chemothera-py. These CSCs would once again be active, with restoration of aresistant tumour phenotype and reestablishment of cytokine andvascular networks (Shigdar et al., 2014); at the same time, inflam-matory cytokines also regulate CSCs and EMT (Ginestier et al., 2010;

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

9T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

Liu et al., 2013; Mitchem et al., 2013; Singh et al., 2013b; Kim et al.,2014a).

Awareness of the evolvability and potential of CSCs to recreatethe tumour microenvironment should direct researchers to developnew therapeutic options targeting the roots of malignancy and notonly cancer cells or CSCs by themselves (Argyle and Blacking, 2008).We advocate that targeting inflammation as the continuous driverfor CSC generation could be an alternative for typically radioresis-tant and chemoresistant cancers, as well as for those tumours wherecancer-related inflammation prevails.

Using non-steroidal anti-inflammatory drugs to ‘kill two birdswith one stone’

The most obvious treatment for cancer-related inflammationwould be the use of non-steroidal anti-inflammatory drugs (NSAIDs),which have been widely used as a therapeutic option in dual mo-dality treatment of cancer patients with colorectal (Thun et al., 2002;Din et al., 2010) and prostatic cancer (Liu et al., 2014). The successof therapy using NSAIDs for human cancers has not yet been rep-licated in dogs (Table 2).

The therapeutic value of NSAIDs for dogs with transitional cellcarcinoma (TCC) of the urinary bladder was studied by Knapp et al.(1992, 1994, 1995). The benefits of NSAIDs (specific or non-specific COX-2 inhibitors), as monotherapy or combined withchemotherapeutic drugs, for the treatment of canine TCC have beensupported by later studies (Henry et al., 2003; McMillan et al., 2011;Knapp et al., 2013; Robat et al., 2013). However, there are con-cerns with the potential side effects of using non-specific COX-2inhibitors; furthermore, not all chemotherapeutic drugs benefit bycombination with adjuvant COX-2 inhibition (Greene et al., 2007;Marconato et al., 2011).

Excluding malignancies of the urinary tract, other canine cancershave been tested in vitro for sensitivity to COX-2 inhibitors. Osteo-sarcoma, glioma, haemangiosarcoma and lymphoma cell lines haveshown sensitivity to mavacoxib and carprofen, as demonstrated byreduced proliferation and increased caspase-independent apopto-sis (Pang et al., 2014). The activity of two non-specific but preferentialCOX-2 inhibitors, etodolac and celecoxib, has also been studied ina canine mammary carcinoma cell line; celecoxib activated the mi-tochondrial apoptosis pathway and caused cell cycle arrest (Saitoet al., 2014). Although some of the effects seen in vitro are at higherconcentrations than can be achieved in vivo, the clinical benefitsmay arise because highly protein bound NSAIDs accumulate in theacidic environment of tumours. Several retrospective studies andclinical trials have examined the therapeutic index of COX-2 inhi-bition, but opinions are divergent for non-urinary tract malignancies(Schmidt et al., 2001; Mutsaers et al., 2002; Sorenmo et al., 2004;Elmslie et al., 2008; Chon et al., 2012; de Vos et al., 2012).

The mechanisms of action of NSAIDs seem to be different ac-cording to the type of COX inhibition and the success of anti-inflammatory drugs appears to derive from their polypharmacology(Liggett et al., 2014). Pang et al. (2014) suggested a central role forCOX-2 in tumour initiation, having identified COX-2 upregulationin CSCs. Even though COX-2 inhibition did not result in reduced vi-ability or chemoresistance in CSCs, tumour sphere formation wasinhibited in both human and canine osteosarcoma cell lines. Al-though the molecular pathways for COX-2 in cancer are not clearlyelucidated, there is a rationale for targeting inflammation based onthis evidence. Within the tumour microenvironment, COX-2 can alsobe produced and amplified by TAMs, promoting tumour progres-sion to advanced metastatic states (Nakao et al., 2005; Hou et al.,2011). It is therefore relevant to target inflammation and its rootsby using NSAIDs active against multiple target genes (Liggett et al.,2014) or by targeting specific multifunctional cell types, such as TAMs(Mitchem et al., 2013).

Conclusions

The intricacies of the complex links between cancer-related in-flammation evolving in a tumour microenvironment deserve ourattention and should be the focus of further research (Fig. 5). Cancerresearch has focussed on tumour cells in isolation for many years;however, it is clear that the whole tumour should be considered asan ecosystem under constant selection pressure. This review hasexamined the key role that inflammation plays in the initiation andpropagation of cancer, and has focussed on some of the cell typesand proteins involved in this process. The key points relating to in-flammation and cancer include: (1) chronic inflammation andsubclinical inflammation (e.g. obesity-induced inflammation) in-creases cancer risk; (2) various types of immune and inflammatorycells are frequently present within tumours; (3) orchestratingcytokines, chemokines and RNS can support tumour initiation, pro-gression and metastatic spread; (4) as tumours develop, anti-tumourigenic and pro-tumourigenic immune and inflammatorymechanisms coexist but, if the tumour is not eradicated, a pro-tumourigenic inflammation predominates; (5) signalling pathwaysthat mediate the pro-tumourigenic effects of inflammation are oftensubject to positive feedback loops (e.g. activation of NF-κB in immunecells induces production of cytokines that activate NF-κB in cancercells to produce chemokines that attract more inflammatory cellsinto the tumour).

Key mediators of inflammation often have dual roles that arecontext dependent, leaving us with a number of specific clinical chal-lenges, including: (1) fully understanding the interplay betweentumour cells, tumour stroma and inflammatory cells; (2) under-standing the tumour microenvironment in which mediators eitherhave a positive or negative influence on tumour propagation; (3)designing specific therapies or therapeutic strategies based aroundthis new understanding. Clinical studies using COX-2 inhibitors areencouraging, but reflect the tip of the iceberg when it comes to un-derstanding how one can manipulate inflammatory cells andpathways to gain a therapeutic advantage. It is clear that the centralrole of inflammation in cancer requires more understanding in orderto develop more efficacious therapeutic options.

Conflict of interest statement

None of the authors of this paper has a financial or personal re-lationship with other people or organisations that couldinappropriately influence or bias the content of the paper.

Acknowledgements

TPR is supported by grants from the Foundation for Science andTechnology, Ministry of Education and Science, Portugal (project noSFRH/BD/79158/2011, QREN – POPH funds). BCBB is funded byCAPES, Ministry of Education, Brazil.

References

Aharinejad, S., Paulus, P., Sioud, M., Hofmann, M., Zins, K., Schafer, R., Stanley, E.R.,Abraham, D., 2004. Colony-stimulating factor-1 blockade by antisenseoligonucleotides and small interfering RNAs suppresses growth of humanmammary tumor xenografts in mice. Cancer Research 64, 5378–5384.

Allenspach, E.J., Maillard, I., Aster, J.C., Pear, W.S., 2002. Notch signaling in cancer.Cancer Biology and Therapy 1, 466–476.

Argyle, D.J., Blacking, T., 2008. From viruses to cancer stem cells: Dissecting thepathways to malignancy. The Veterinary Journal 177, 311–323.

Atsumi, T., Singh, R., Sabharwal, L., Bando, H., Meng, J., Arima, Y., Yamada, M., Harada,M., Jiang, J.J., Kamimura, D., et al., 2014. Inflammation amplifier, a new paradigmin cancer biology. Cancer Research 74, 8–14.

Baj-Krzyworzeka, M., Baran, J., Weglarczyk, K., Szatanek, R., Szaflarska, A., Siedlar,M., Zembala, M., 2010. Tumour-derived microvesicles (TMV) mimic the effectof tumour cells on monocyte subpopulations. Anticancer Research 30, 3515–3519.

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

10 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

Baj-Krzyworzeka, M., Weglarczyk, K., Mytar, B., Szatanek, R., Baran, J., Zembala, M.,2011. Tumour-derived microvesicles contain interleukin-8 and modulateproduction of chemokines by human monocytes. Anticancer Research 31,1329–1335.

Balkwill, F., 2004. Cancer and the chemokine network. Nature Reviews. Cancer 4,540–550.

Balkwill, F., Mantovani, A., 2001. Inflammation and cancer: Back to Virchow? TheLancet 357, 539–545.

Balkwill, F., Charles, K.A., Mantovani, A., 2005. Smoldering and polarized inflammationin the initiation and promotion of malignant disease. Cancer Cell 7, 211–217.

Bartocci, A., Mastrogiannis, D.S., Migliorati, G., Stockert, R.J., Wolkoff, A.W., Stanley,E.R., 1987. Macrophages specifically regulate the concentration of their owngrowth factor in the circulation. Proceedings of the National Academy of Sciencesof the United States of America 84, 6179–6183.

Beatty, J., 2014. Viral causes of feline lymphoma: Retroviruses and beyond. TheVeterinary Journal 201, 174–180.

Ben-Neriah, Y., Karin, M., 2011. Inflammation meets cancer, with NF-κB as thematchmaker. Nature Immunology 12, 715–723.

Benoy, I.H., Salgado, R., Van, D.P., Geboers, K., Van, M.E., Scharpe, S., Vermeulen, P.B.,Dirix, L.Y., 2004. Increased serum interleukin-8 in patients with early andmetastatic breast cancer correlates with early dissemination and survival. ClinicalCancer Research 10, 7157–7162.

Boria, P.A., Murry, D.J., Bennett, P.F., Glickman, N.W., Snyder, P.W., Merkel, B.L.,Schlittler, D.L., Mutsaers, A.J., Thomas, R.M., Knapp, D.W., 2004. Evaluation ofcisplatin combined with piroxicam for the treatment of oral malignant melanomaand oral squamous cell carcinoma in dogs. Journal of the American VeterinaryMedical Association 224, 388–394.

Boveri, T., 2008. Concerning the origin of malignant tumours by Theodor Boveri.Translated and annotated by Henry Harris. Journal of Cell Science 121, 1–84.

Brien, G., Trescol-Biemont, M.C., Bonnefoy-Bérard, N., 2007. Downregulation of Bfl-1protein expression sensitizes malignant B cells to apoptosis. Oncogene 26,5828–5832.

Bronte, V., Serafini, P., Apolloni, E., Zanovello, P., 2001. Tumor-induced immunedysfunctions caused by myeloid suppressor cells. Journal of Immunotherapy 24,431–446.

Brown, K.D., 2013. Transglutaminase 2 and NF-κB: An odd couple that shapes breastcancer phenotype. Breast Cancer Research and Treatment 137, 329–336.

Calle, E.E., Kaaks, R., 2004. Overweight, obesity and cancer: Epidemiological evidenceand proposed mechanisms. Nature Reviews. Cancer 4, 579–591.

Carnero, A., Blanco-Aparicio, C., Renner, O., Link, W., Leal, J.F., 2008. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Current Cancer DrugTargets 8, 187–198.

Carvalho, M.I., Pires, I., Prada, J., Queiroga, F.L., 2011. T-lymphocytic infiltrate in caninemammary tumours: Clinic and prognostic implications. In Vivo (Athens, Greece)25, 963–969.

Cerchietti, L.C., Bonomi, M.R., Navigante, A.H., Castro, M.A., Cabalar, M.E., Roth, B.M.,2005. Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as aradiation sensitizer in patients with unresectable brain metastases. Journal ofNeurooncology 71, 73–81.

Cervantes-Arias, A., Pang, L.Y., Argyle, D.J., 2013. Epithelial-mesenchymal transitionas a fundamental mechanism underlying the cancer phenotype. Veterinary andComparative Oncology 11, 169–184.

Chase, D., McLauchlan, G., Eckersall, P.D., Pratschke, J., Parkin, T., Pratschke, K., 2012.Acute phase protein levels in dogs with mast cell tumours and sarcomas.Veterinary Record 170, 648.

Chaturvedi, M.M., Sung, B., Yadav, V.R., Kannappan, R., Aggarwal, B.B., 2011. NF-κBaddiction and its role in cancer: ‘One size does not fit all’. Oncogene 30,1615–1630.

Chitu, V., Stanley, E.R., 2006. Colony-stimulating factor-1 in immunity andinflammation. Current Opinion in Immunology 18, 39–48.

Chon, E., McCartan, L., Kubicek, L.N., Vail, D.M., 2012. Safety evaluation of combinationtoceranib phosphate (Palladia®) and piroxicam in tumour-bearing dogs (excludingmast cell tumours): A phase I dose-finding study. Veterinary and ComparativeOncology 10, 184–193.

Cohen, A.J., Pope, C.A., 1995. Lung cancer and air pollution. Environmental HealthPerspectives 103, 219–224.

Colotta, F., Allavena, P., Sica, A., Garlanda, C., Mantovani, A., 2009. Cancer-relatedinflammation, the seventh hallmark of cancer: Links to genetic instability.Carcinogenesis 30, 1073–1081.

Coussens, L.M., Werb, Z., 2002. Inflammation and cancer. Nature 420, 860–867.Cross, S.S., Hamdy, F.C., Deloulme, J.C., Rehman, I., 2005. Expression of S100 proteins

in normal human tissues and common cancers using tissue microarrays: S100A6,S100A8, S100A9 and S100A11 are all overexpressed in common cancers.Histopathology 46, 256–269.

Csermely, P., Hodsagi, J., Korcsmaros, T., Modos, D., Perez-Lopez, A.R., Szalay, K., Veres,D.V., Lenti, K., Wu, L.Y., Zhang, X.S., 2014. Cancer stem cells display extremelylarge evolvability: Alternating plastic and rigid networks as a potentialmechanism: Network models, novel therapeutic target strategies, and thecontributions of hypoxia, inflammation and cellular senescence. Seminars inCancer Biology 30, 42–51.

de Andres, P.J., Illera, J.C., Caceres, S., Diez, L., Perez-Alenza, M.D., Pena, L., 2013.Increased levels of interleukins 8 and 10 as findings of canine inflammatorymammary cancer. Veterinary Immunology and Immunopathology 152, 245–251.

de Vos, J., Ramos, V.S., Noorman, E., de Vos, P., 2012. Primary frontal sinus squamouscell carcinoma in three dogs treated with piroxicam combined with carboplatinor toceranib. Veterinary and Comparative Oncology 10, 206–213.

Das, K.C., White, C.W., 1997. Activation of NF-κB by antineoplastic agents. Journalof Biological Chemistry 272, 14914–14920.

De Falco, M., Lucariello, A., Iaquinto, S., Esposito, V., Guerra, G., De Luca, A., 2015.Molecular mechanisms of Helicobacter pylori pathogenesis. Journal of CellPhysiology doi:10.1002/jcp.24933.

Debucquoy, A., Roels, S., Goethals, L., Libbrecht, L., Van, C.E., Geboes, K., Penninckx,F., D’Hoore, A., McBride, W.H., Haustermans, K., 2009. Double blind randomizedphase II study with radiation+5-fluorouracil+/-celecoxib for resectable rectalcancer. Radiotherapy and Oncology 93, 273–278.

Dethlefsen, C., Hojfeldt, G., Hojman, P., 2013. The role of intratumoral and systemicIL-6 in breast cancer. Breast Cancer Research and Treatment 138, 657–664.

Din, F.V., Theodoratou, E., Farrington, S.M., Tenesa, A., Barnetson, R.A., Cetnarskyj,R., Stark, L., Porteous, M.E., Campbell, H., Dunlop, M.G., 2010. Effect of aspirinand NSAIDs on risk and survival from colorectal cancer. Gut 59, 1670–1679.

Dvorak, H.F., 1986. Tumors: Wounds that do not heal. Similarities between tumorstroma generation and wound healing. New England Journal of Medicine 315,1650–1659.

Elmets, C.A., Viner, J.L., Pentland, A.P., Cantrell, W., Lin, H.Y., Bailey, H., Kang, S., Linden,K.G., Heffernan, M., Duvic, M., et al., 2010. Chemoprevention of nonmelanomaskin cancer with celecoxib: A randomized, double-blind, placebo-controlled trial.Journal of the National Cancer Institute 102, 1835–1844.

Elmslie, R.E., Glawe, P., Dow, S.W., 2008. Metronomic therapy with cyclophosphamideand piroxicam effectively delays tumor recurrence in dogs with incompletelyresected soft tissue sarcomas. Journal of Veterinary Internal Medicine 22,1373–1379.

Escárcega, R.O., Fuentes-Alexandro, S., García-Carrasco, M., Gatica, A., Zamora, A., 2007.The transcription factor nuclear factor-κB and cancer. Clinical Oncology 19,154–161.

Estrela-Lima, A., Araujo, M.S., Costa-Neto, J.M., Teixeira-Carvalho, A., Barrouin-Melo,S.M., Cardoso, S.V., Martins-Filho, O.A., Serakides, R., Cassali, G.D., 2010.Immunophenotypic features of tumor infiltrating lymphocytes from mammarycarcinomas in female dogs associated with prognostic factors and survival rates.BMC Cancer 10, 256.

Fabi, A., Metro, G., Papaldo, P., Mottolese, M., Melucci, E., Carlini, P., Sperduti, I., Russillo,M., Gelibter, A., Ferretti, G., et al., 2008. Impact of celecoxib on capecitabinetolerability and activity in pretreated metastatic breast cancer: Results of a phaseII study with biomarker evaluation. Cancer Chemotherapy and Pharmacology62, 717–725.

Fang, J.Y., Richardson, B.C., 2005. The MAPK signalling pathways and colorectal cancer.The Lancet Oncology 6, 322–327.

Fang, W.B., Jokar, I., Zou, A., Lambert, D., Dendukuri, P., Cheng, N., 2012. CCL2/CCR2chemokine signaling coordinates survival and motility of breast cancer cellsthrough Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. Journal of Biological Chemistry 287, 36593–36608.

Francescone, R., Hou, V., Grivennikov, S.I., 2015. Cytokines, IBD, and colitis-associatedcancer. Inflammatory Bowel Disease 21, 409–418.

Fujimoto, H., Sangai, T., Ishii, G., Ikehara, A., Nagashima, T., Miyazaki, M., Ochiai, A.,2009. Stromal MCP-1 in mammary tumors induces tumor-associated macrophageinfiltration and contributes to tumor progression. International Journal of Cancer125, 1276–1284.

Gelaleti, G.B., Jardim, B.V., Leonel, C., Moschetta, M.G., Zuccari, D.A., 2012. Interleukin-8as a prognostic serum marker in canine mammary gland neoplasias. VeterinaryImmunology and Immunopathology 146, 106–112.

Ginestier, C., Liu, S., Diebel, M.E., Korkaya, H., Luo, M., Brown, M., Wicinski, J., Cabaud,O., Charafe-Jauffret, E., Birnbaum, D., et al., 2010. CXCR1 blockade selectivelytargets human breast cancer stem cells in vitro and in xenografts. Journal ofClinical Investigation 120, 485–497.

Greene, S.N., Lucroy, M.D., Greenberg, C.B., Bonney, P.L., Knapp, D.W., 2007. Evaluationof cisplatin administered with piroxicam in dogs with transitional cell carcinomaof the urinary bladder. Journal of the American Veterinary Medical Association231, 1056–1060.

Grivennikov, S.I., Greten, F.R., Karin, M., 2010. Immunity, inflammation, and cancer.Cell 140, 883–899.

Gupta, S.C., Hevia, D., Patchva, S., Park, B., Koh, W., Aggarwal, B.B., 2012. Upsides anddownsides of reactive oxygen species for cancer: The roles of reactive oxygenspecies in tumorigenesis, prevention, and therapy. Antioxidants and RedoxSignaling 16, 1295–1322.

Hagemann, T., Biswas, S.K., Lawrence, T., Sica, A., Lewis, C.E., 2009. Regulation ofmacrophage function in tumors: The multifaceted role of NF-κB. Blood 113,3139–3146.

Hanahan, D., Weinberg, R.A., 2000. The hallmarks of cancer. Cell 100, 57–70.Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: The next generation. Cell

144, 646–674.Hansen, M.T., Forst, B., Cremers, N., Quagliata, L., Ambartsumian, N., Grum-Schwensen,

B., Klingelhofer, J., Abdul-Al, A., Herrmann, P., Osterland, M., et al., 2014. A linkbetween inflammation and metastasis: Serum amyloid A1 and A3 inducemetastasis, and are targets of metastasis-inducing S100A4. Oncogene 34,424–435.

Hashimoto, S.I., Komuro, I., Yamada, M., Akagawa, K.S., 2001. IL-10 inhibitsgranulocyte-macrophage colony-stimulating factor-dependent human monocytesurvival at the early stage of the culture and inhibits the generation ofmacrophages. Journal of Immunology 167, 3619–3625.

Heilmann, R.M., Wright, Z.M., Lanerie, D.J., Suchodolski, J.S., Steiner, J.M., 2014.Measurement of urinary canine S100A8/A9 and S100A12 concentrations ascandidate biomarkers of lower urinary tract neoplasia in dogs. Journal ofVeterinary Diagnostic Investigation 26, 104–112.

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

11T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

Hembruff, S.L., Jokar, I., Yang, L., Cheng, N., 2010. Loss of transforming growthfactor-beta signaling in mammary fibroblasts enhances CCL2 secretion to promotemammary tumor progression through macrophage-dependent and -independentmechanisms. Neoplasia 12, 425–433.

Henry, C.J., McCaw, D.L., Turnquist, S.E., Tyler, J.W., Bravo, L., Sheafor, S., Straw, R.C.,Dernell, W.S., Madewell, B.R., Jorgensen, L., et al., 2003. Clinical evaluation ofmitoxantrone and piroxicam in a canine model of human invasive urinary bladdercarcinoma. Clinical Cancer Research 9, 906–911.

Hiratsuka, S., Ishibashi, S., Tomita, T., Watanabe, A., Akashi-Takamura, S., Murakami,M., Kijima, H., Miyake, K., Aburatani, H., Maru, Y., 2013. Primary tumours modulateinnate immune signalling to create pre-metastatic vascular hyperpermeabilityfoci. Nature Communications 4, 1853.

Hiscott, J., Kwon, H., Génin, P., 2001. Hostile takeovers: Viral appropriation of theNF-κB pathway. Journal of Clinical Investigation 107, 143–151.

Hiwatashi, K., Tamiya, T., Hasegawa, E., Fukaya, T., Hashimoto, M., Kakoi, K., Kashiwagi,I., Kimura, A., Inoue, N., Morita, R., et al., 2011. Suppression of SOCS3 inmacrophages prevents cancer metastasis by modifying macrophage phase andMCP2/CCL8 induction. Cancer Letters 308, 172–180.

Hoesel, B., Schmid, J.A., 2013. The complexity of NF-κB signaling in inflammationand cancer. Molecular Cancer 12, 86.

Hou, Z., Falcone, D.J., Subbaramaiah, K., Dannenberg, A.J., 2011. Macrophages induceCOX-2 expression in breast cancer cells: Role of IL-1β autoamplification.Carcinogenesis 32, 695–702.

Hsiao, Y.W., Liao, K.W., Chung, T.F., Liu, C.H., Hsu, C.D., Chu, R.M., 2008. Interactionsof host IL-6 and IFN-γ and cancer-derived TGF-β1 on MHC molecule expressionduring tumor spontaneous regression. Cancer Immunology, Immunotherapy 57,1091–1104.

Hsu, R.Y., Chan, C.H., Spicer, J.D., Rousseau, M.C., Giannias, B., Rousseau, S., Ferri, L.E.,2011. LPS-induced TLR4 signaling in human colorectal cancer cells increases β1integrin-mediated cell adhesion and liver metastasis. Cancer Research 71,1989–1998.

Ishioka, K., Suzuki, Y., Tajima, K., Ohtaki, S., Miyabe, M., Takasaki, M., Mori, A., Momota,Y., Azakami, D., Sako, T., 2012. Monocyte chemoattractant protein-1 in dogsaffected with neoplasia or inflammation. Journal of Veterinary Medical Science75, 173–177.

Joyce, J.A., Pollard, J.W., 2009. Microenvironmental regulation of metastasis. NatureReviews Cancer 9, 239–252.

Kamradt, T., 2012. Immunological tolerance. In: Male, D., Brostoff, J., Roth,D., Roitt, I. (Eds.), Immunology, Eighth Ed. Elsevier, St. Louis, MO, USA, pp.307–321.

Karin, M., 2006. Nuclear factor-κB in cancer development and progression. Nature441, 431–436.

Karin, M., 2008. The IκB kinase – a bridge between inflammation and cancer. CellResearch 18, 334–342.

Keniry, M., Parsons, R., 2008. The role of PTEN signaling perturbations in cancer andin targeted therapy. Oncogene 27, 5477–5485.

Kim, J.H., Yu, C.H., Yhee, J.Y., Im, K.S., Sur, J.H., 2010. Lymphocyte infiltration, expressionof interleukin (IL) -1, IL-6 and expression of mutated breast cancer susceptibilitygene-1 correlate with malignancy of canine mammary tumours. Journal ofComparative Pathology 142, 177–186.

Kim, G., Ouzounova, M., Quraishi, A.A., Davis, A., Tawakkol, N., Clouthier, S.G., Malik,F., Paulson, A.K., D’Angelo, R.C., Korkaya, S., et al., 2014a. SOCS3-mediatedregulation of inflammatory cytokines in PTEN and p53 inactivated triple negativebreast cancer model. Oncogene 34, 671–680.

Kim, J.H., Frantz, A.M., Anderson, K.L., Graef, A.J., Scott, M.C., Robinson, S., Sharkey,L.C., O’Brien, T.D., Dickerson, E.B., Modiano, J.F., 2014b. Interleukin-8 promotescanine hemangiosarcoma growth by regulating the tumor microenvironment.Experimental Cell Research 323, 155–164.

Kipanyula, M.J., Seke Etet, P.F., Vecchio, L., Farahna, M., Nukenine, E.N., Nwabo Kamdje,A.H., 2013. Signaling pathways bridging microbial-triggered inflammation andcancer. Cellular Signalling 25, 403–416.

Knapp, D.W., Richardson, R.C., Bottoms, G.D., Teclaw, R., Chan, T.C., 1992. Phase I trialof piroxicam in 62 dogs bearing naturally occurring tumors. Cancer Chemotherapyand Pharmacology 29, 214–218.

Knapp, D.W., Richardson, R.C., Chan, T.C., Bottoms, G.D., Widmer, W.R., DeNicola, D.B.,Teclaw, R., Bonney, P.L., Kuczek, T., 1994. Piroxicam therapy in 34 dogs withtransitional cell carcinoma of the urinary bladder. Journal of Veterinary InternalMedicine 8, 273–278.

Knapp, D.W., Chan, T.C., Kuczek, T., Reagan, W.J., Park, B., 1995. Evaluation of in vitrocytotoxicity of nonsteroidal anti-inflammatory drugs against canine tumor cells.American Journal of Veterinary Research 56, 801–805.

Knapp, D.W., Henry, C.J., Widmer, W.R., Tan, K.M., Moore, G.E., Ramos-Vara, J.A., Lucroy,M.D., Greenberg, C.B., Greene, S.N., Abbo, A.H., et al., 2013. Randomized trial ofcisplatin versus firocoxib versus cisplatin/firocoxib in dogs with transitional cellcarcinoma of the urinary bladder. Journal of Veterinary Internal Medicine 27,126–133.

Koizumi, K., Hojo, S., Akashi, T., Yasumoto, K., Saiki, I., 2007. Chemokine receptorsin cancer metastasis and cancer cell-derived chemokines in host immuneresponse. Cancer Science 98, 1652–1658.

Krol, M., Pawlowski, K.M., Dolka, I., Musielak, O., Majchrzak, K., Mucha, J., Motyl, T.,2011a. Density of Gr1-positive myeloid precursor cells, p-STAT3 expression andgene expression pattern in canine mammary cancer metastasis. VeterinaryResearch Communications 35, 409–423.

Krol, M., Pawlowski, K.M., Majchrzak, K., Dolka, I., Abramowicz, A., Szyszko, K., Motyl,T., 2011b. Density of tumor-associated macrophages (TAMs) and expressionof their growth factor receptor MCSF-R and CD14 in canine mammary

adenocarcinomas of various grade of malignancy and metastasis. Polish Journalof Veterinary Sciences 14, 3–10.

Krol, M., Majchrzak, K., Mucha, J., Homa, A., Bulkowska, M., Jakubowska, A., Karwicka,M., Pawlowski, K.M., Motyl, T., 2013. CSF-1R as an inhibitor of apoptosis andpromoter of proliferation, migration and invasion of canine mammary cancercells. BMC Veterinary Research 9, 65.

Landskron, G., De la Fuente, M., Thuwajit, P., Thuwajit, C., Hermoso, M.A., 2014. Chronicinflammation and cytokines in the tumor microenvironment. Journal ofImmunology Research 2014, 149185.

Lane, P.J., McConnell, F.M., Anderson, G., Nawaf, M.G., Gaspal, F.M., Withers, D.R., 2014.Evolving strategies for cancer and autoimmunity: Back to the future. Frontiersin Immunology 5, 154.

Lejeune, F.J., Monnier, Y., Ruegg, C., 2006. Complete and long-lasting regression ofdisseminated multiple skin melanoma metastases under treatment withcyclooxygenase-2 inhibitor. Melanoma Research 16, 263–265.

Lentsch, A.B., Shanley, T.P., Sarma, V., Ward, P.A., 1997. In vivo suppression of NF-κBand preservation of IκBα by interleukin-10 and interleukin-13. Journal of ClinicalInvestigation 100, 2443–2448.

Lewis, C.E., Pollard, J.W., 2006. Distinct role of macrophages in different tumormicroenvironments. Cancer Research 66, 605–612.

Li, S., Symonds, A.L., Miao, T., Sanderson, I., Wang, P., 2014. Modulation of antigen-specific T-cells as immune therapy for chronic infectious diseases and cancer.Frontiers in Immunology 5, 293.

Li, Z., Xu, Q., Peng, H., Cheng, R., Sun, Z., Ye, Z., 2011. IFN-γ enhances HOS and U2OScell lines susceptibility to γδ T cell-mediated killing through the Fas/Fas ligandpathway. International Immunopharmacology 11, 496–503.

Liggett, J.L., Zhang, X., Eling, T.E., Baek, S.J., 2014. Anti-tumor activity of non-steroidalanti-inflammatory drugs: Cyclooxygenase-independent targets. Cancer Letters346, 217–224.

Lin, E.Y., Li, J.F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D.A., Qian, H., Xue, X.N., Pollard,J.W., 2006. Macrophages regulate the angiogenic switch in a mouse model ofbreast cancer. Cancer Research 66, 11238–11246.

Lin, C.S., Chen, M.F., Wang, Y.S., Chuang, T.F., Chiang, Y.L., Chu, R.M., 2013. IL-6 restoresdendritic cell maturation inhibited by tumor-derived TGF-β through interferingSmad 2/3 nuclear translocation. Cytokine 62, 352–359.

Ling, J., Kumar, R., 2012. Crosstalk between NFkB and glucocorticoid signaling: Apotential target of breast cancer therapy. Cancer Letters 322, 119–126.

Liu, W.H., Liu, J.J., Wu, J., Zhang, L.L., Liu, F., Yin, L., Zhang, M.M., Yu, B., 2013. Novelmechanism of inhibition of dendritic cells maturation by mesenchymal stem cellsvia interleukin-10 and the JAK1/STAT3 signaling pathway. PLoS ONE 8, e55487.

Liu, Y., Chen, J.Q., Xie, L., Wang, J., Li, T., He, Y., Gao, Y., Qin, X., Li, S., 2014. Effect ofaspirin and other non-steroidal anti-inflammatory drugs on prostate cancerincidence and mortality: A systematic review and meta-analysis. BMC Medicine12, 55.

Loberg, R.D., Ying, C., Craig, M., Day, L.L., Sargent, E., Neeley, C., Wojno, K., Snyder,L.A., Yan, L., Pienta, K.J., 2007. Targeting CCL2 with systemic delivery ofneutralizing antibodies induces prostate cancer tumor regression in vivo. CancerResearch 67, 9417–9424.

Lu, X., Kang, Y., 2009. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cellsof monocytic origin to promote breast cancer metastasis to lung and bone. Journalof Biological Chemistry 284, 29087–29096.

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

Marconato, L., Zini, E., Lindner, D., Suslak-Brown, L., Nelson, V., Jeglum, A.K., 2011.Toxic effects and antitumor response of gemcitabine in combination withpiroxicam treatment in dogs with transitional cell carcinoma of the urinarybladder. Journal of the American Veterinary Medical Association 238, 1004–1010.

Markowitz, J., Wesolowski, R., Papenfuss, T., Brooks, T.R., Carson, W.E., III, 2013.Myeloid-derived suppressor cells in breast cancer. Breast Cancer Research andTreatment 140, 13–21.

Maruyama, K., Ii, M., Cursiefen, C., Jackson, D.G., Keino, H., Tomita, M., Van, R.N.,Takenaka, H., D’Amore, P.A., Stein-Streilein, J., et al., 2005. Inflammation-inducedlymphangiogenesis in the cornea arises from CD11b-positive macrophages.Journal of Clinical Investigation 115, 2363–2372.

McMillan, S.K., Boria, P., Moore, G.E., Widmer, W.R., Bonney, P.L., Knapp, D.W., 2011.Antitumor effects of deracoxib treatment in 26 dogs with transitional cellcarcinoma of the urinary bladder. Journal of the American Veterinary MedicalAssociation 239, 1084–1089.

Melichar, B., Študentova, H., Kalábová, H., Vitásková, D., Cermáková, P., Hornychová,H., Ryška, A., 2014. Predictive and prognostic significance of tumor-infiltratinglymphocytes in patients with breast cancer treated with neoadjuvant systemictherapy. Anticancer Research 34, 1115–1125.

Mitchell, R.A., Bucala, R., 2000. Tumor growth-promoting properties of macrophagemigration inhibitory factor (MIF). Seminars in Cancer Biology 10, 359–366.

Mitchem, J.B., Brennan, D.J., Knolhoff, B.L., Belt, B.A., Zhu, Y., Sanford, D.E., Belaygorod,L., Carpenter, D., Collins, L., Piwnica-Worms, D., et al., 2013. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relievesimmunosuppression, and improves chemotherapeutic responses. Cancer Research73, 1128–1141.

Mkaouar, L., Endo, Y., Mochizuki, M., Nishimura, R., Sasaki, N., Nakagawa, T., 2011.Effects of NF-κB expression and its inhibition on canine mammary cancer celllines in an immunodeficient mice model. Journal of Veterinary Medical Science73, 1539–1546.

Mkaouar, L., Endo, Y., Jun, H.X., Lee, S.J., Jaroensong, T., Mochizuki, M., Uchida, K.,Nakayama, H., Sasaki, N., Nakagawa, T., 2012. Relationship between NF-κB

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

12 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

expression and malignancy of canine mammary gland tumor tissues. Journal ofVeterinary Medical Science 74, 713–718.

Modiano, J.F., Bellgrau, D., Cutter, G.R., Lana, S.E., Ehrhart, N.P., Ehrhart, E., Wilke, V.L.,Charles, J.B., Munson, S., Scott, M.C., et al., 2012. Inflammation, apoptosis, andnecrosis induced by neoadjuvant Fas ligand gene therapy improves survival ofdogs with spontaneous bone cancer. Molecular Therapy 20, 2234–2243.

Mudaliar, M.A., Haggart, R.D., Miele, G., Sellar, G., Tan, K.A., Goodlad, J.R., Milne, E.,Vail, D.M., Kurzman, I., Crowther, D., et al., 2013. Comparative gene expressionprofiling identifies common molecular signatures of NF-κB activation in canineand human diffuse large B cell lymphoma (DLBCL). PLoS ONE 8, e72591.

Mumm, J.B., Oft, M., 2013. Pegylated IL-10 induces cancer immunity: The surprisingrole of IL-10 as a potent inducer of IFN-γ-mediated CD8+ T cell cytotoxicity.Bioessays: News and Reviews in Molecular, Cellular and Developmental Biology35, 623–631.

Mumm, J.B., Emmerich, J., Zhang, X., Chan, I., Wu, L., Mauze, S., Blaisdell, S., Basham,B., Dai, J., Grein, J., et al., 2011. IL-10 elicits IFNγ-dependent tumor immunesurveillance. Cancer Cell 20, 781–796.

Munro, A.J., Lain, S., Lane, D.P., 2005. P53 abnormalities and outcomes in colorectalcancer: A systematic review. British Journal of Cancer 92, 434–444.

Muranski, P., Restifo, N.P., 2013. Essentials of Th17 cell commitment and plasticity.Blood 121, 2402–2414.

Mutsaers, A.J., Glickman, N.W., DeNicola, D.B., Widmer, W.R., Bonney, P.L., Hahn, K.A.,Knapp, D.W., 2002. Evaluation of treatment with doxorubicin and piroxicam ordoxorubicin alone for multicentric lymphoma in dogs. Journal of the AmericanVeterinary Medical Association 220, 1813–1817.

Nakanishi, C., Toi, M., 2005. Nuclear factor-κB inhibitors as sensitizers to anticancerdrugs. Nature Reviews. Cancer 5, 297–309.

Nakao, S., Kuwano, T., Tsutsumi-Miyahara, C., Ueda, S., Kimura, Y.N., Hamano, S.,Sonoda, K.H., Saijo, Y., Nukiwa, T., Strieter, R.M., et al., 2005. Infiltration ofCOX-2-expressing macrophages is a prerequisite for IL-1β-inducedneovascularization and tumor growth. Journal of Clinical Investigation 115,2979–2991.

Nikolic, N.L., Kjelgaard-Hansen, M., Kristensen, A.T., 2013. Monocyte chemotacticprotein-1 and other inflammatory parameters in Bernese mountain dogs withdisseminated histiocytic sarcoma. The Veterinary Journal 198, 424–428.

Obeid, E., Nanda, R., Fu, Y.X., Olopade, O.I., 2013. The role of tumor-associatedmacrophages in breast cancer progression. International Journal of Oncology 43,5–12.

Ohnishi, S., Ma, N., Thanan, R., Pinlaor, S., Hammam, O., Murata, M., Kawanishi, S.,2013. DNA damage in inflammation-related carcinogenesis and cancer stem cells.Oxidative Medicine and Cellular Longevity 2013, 387014.

Ohno, S., Ohno, Y., Suzuki, N., Kamei, T., Koike, K., Inagawa, H., Kohchi, C., Soma, G.,Inoue, M., 2004. Correlation of histological localization of tumor-associatedmacrophages with clinicopathological features in endometrial cancer. AnticancerResearch 24, 3335–3342.

Ohta, H., Takada, K., Sunden, Y., Tamura, Y., Osuga, T., Lim, S.Y., Murakami, M., Sasaki,N., Wickramasekara Rajapakshage, B.K., Nakamura, K., et al., 2014. CD4+ T cellcytokine gene and protein expression in duodenal mucosa of dogs withinflammatory bowel disease. Journal of Veterinary Medical Science 76, 409–414.

Osaki, M., Oshimura, M., Ito, H., 2004. PI3K-Akt pathway: Its functions and alterationsin human cancer. Apoptosis: An International Journal on Programmed Cell Death9, 667–676.

Pai, R., Soreghan, B., Szabo, I.L., Pavelka, M., Baatar, D., Tarnawski, A.S., 2002.Prostaglandin E2 transactivates EGF receptor: A novel mechanism for promotingcolon cancer growth and gastrointestinal hypertrophy. Nature Medicine 8,289–293.

Pang, L.Y., Gatenby, E.L., Kamida, A., Whitelaw, B.A., Hupp, T.R., Argyle, D.J., 2014.Global gene expression analysis of canine osteosarcoma stem cells reveals a novelrole for COX-2 in tumour initiation. PLoS ONE 9, e83144.

Paoloni, M., Davis, S., Lana, S., Withrow, S., Sangiorgi, L., Picci, P., Hewitt, S., Triche,T., Meltzer, P., Khanna, C., 2009. Canine tumor cross-species genomics uncoverstargets linked to osteosarcoma progression. BMC Genomics 10, 625.

Patsialou, A., Wyckoff, J., Wang, Y., Goswami, S., Stanley, E.R., Condeelis, J.S., 2009.Invasion of human breast cancer cells in vivo requires both paracrine andautocrine loops involving the colony-stimulating factor-1 receptor. CancerResearch 69, 9498–9506.

Pei, X.H., Nakanishi, Y., Takayama, K., Bai, F., Hara, N., 1999. Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors can stimulate theinvasive capacity of human lung cancer cells. British Journal of Cancer 79, 40–46.

Perry, J.A., Thamm, D.H., Eickhoff, J., Avery, A.C., Dow, S.W., 2011. Increased monocytechemotactic protein-1 concentration and monocyte count independentlyassociate with a poor prognosis in dogs with lymphoma. Veterinary andComparative Oncology 9, 55–64.

Polverini, P.J., Leibovich, S.J., 1984. Induction of neovascularization in vivo andendothelial proliferation in vitro by tumor-associated macrophages. LaboratoryInvestigation 51, 635–642.

Prior, I.A., Lewis, P.D., Mattos, C., 2012. A comprehensive survey of Ras mutationsin cancer. Cancer Research 72, 2457–2467.

Qian, B., Deng, Y., Im, J.H., Muschel, R.J., Zou, Y., Li, J., Lang, R.A., Pollard, J.W., 2009.A distinct macrophage population mediates metastatic breast cancer cellextravasation, establishment and growth. PLoS ONE 4, e6562.

Qian, B.Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L.R., Kaiser, E.A., Snyder,L.A., Pollard, J.W., 2011. CCL2 recruits inflammatory monocytes to facilitatebreast-tumour metastasis. Nature 475, 222–225.

Qian, B.Z., Pollard, J.W., 2012. New tricks for metastasis-associated macrophages.Breast Cancer Research 14, 316.

Raposo, T.P., Pires, I., Carvalho, M.I., Prada, J., Argyle, D.J., Queiroga, F.L., 2013.Tumour-associated macrophages are associated with vascular endothelial growthfactor expression in canine mammary tumours. Veterinary and ComparativeOncology doi:10.1111/vco.12067.

Raposo, T., Gregorio, H., Pires, I., Prada, J., Queiroga, F.L., 2014. Prognostic value oftumour-associated macrophages in canine mammary tumours. Veterinary andComparative Oncology 12, 10–19.

Robat, C., Burton, J., Thamm, D., Vail, D., 2013. Retrospective evaluation ofdoxorubicin-piroxicam combination for the treatment of transitional cellcarcinoma in dogs. Journal of Small Animal Practice 54, 67–74.

Robinson, B.D., Sica, G.L., Liu, Y.F., Rohan, T.E., Gertler, F.B., Condeelis, J.S., Jones, J.G.,2009. Tumor microenvironment of metastasis in human breast carcinoma: Apotential prognostic marker linked to hematogenous dissemination. ClinicalCancer Research 15, 2433–2441.

Saito, T., Tamura, D., Asano, R., 2014. Usefulness of selective COX-2 inhibitors astherapeutic agents against canine mammary tumors. Oncology Reports 31,1637–1644.

Schmidt, B.R., Glickman, N.W., DeNicola, D.B., de Gortari, A.E., Knapp, D.W., 2001.Evaluation of piroxicam for the treatment of oral squamous cell carcinoma indogs. Journal of the American Veterinary Medical Association 218, 1783–1786.

Schwandt, A., Garcia, J.A., Elson, P., Wyckhouse, J., Finke, J.H., Ireland, J., Triozzi, P.,Zhou, M., Dreicer, R., Rini, B.I., 2011. Clinical and immunomodulatory effects ofcelecoxib plus interferon-α in metastatic renal cell carcinoma patients with COX-2tumor immunostaining. Journal of Clinical Immunology 31, 690–698.

Sester, D.P., Beasley, S.J., Sweet, M.J., Fowles, L.F., Cronau, S.L., Stacey, K.J., Hume, D.A.,1999. Bacterial/CpG DNA down-modulates colony stimulating factor-1 receptorsurface expression on murine bone marrow-derived macrophages withconcomitant growth arrest and factor-independent survival. Journal ofImmunology 163, 6541–6550.

Sheng, H., Shao, J., Washington, M.K., DuBois, R.N., 2001. Prostaglandin E2 increasesgrowth and motility of colorectal carcinoma cells. Journal of Biological Chemistry276, 18075–18081.

Shigdar, S., Li, Y., Bhattacharya, S., O’Connor, M., Pu, C., Lin, J., Wang, T., Xiang, D.,Kong, L., Wei, M.Q., et al., 2014. Inflammation and cancer stem cells. Cancer Letters345, 271–278.

Sica, A., Schioppa, T., Mantovani, A., Allavena, P., 2006. Tumour-associatedmacrophages are a distinct M2 polarised population promoting tumourprogression: Potential targets of anti-cancer therapy. European Journal of Cancer42, 717–727.

Singh, B., Berry, J.A., Vincent, L.E., Lucci, A., 2006. Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer. Journal of Surgical Research 134,44–51.

Singh, J.K., Farnie, G., Bundred, N.J., Simoes, B.M., Shergill, A., Landberg, G., Howell,S.J., Clarke, R.B., 2013a. Targeting CXCR1/2 significantly reduces breast cancerstem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clinical Cancer Research 19, 643–656.

Singh, J.K., Simoes, B.M., Howell, S.J., Farnie, G., Clarke, R.B., 2013b. Recent advancesreveal IL-8 signaling as a potential key to targeting breast cancer stem cells. BreastCancer Research 15, 210.

Sinha, P., Clements, V.K., Fulton, A.M., Ostrand-Rosenberg, S., 2007. Prostaglandin E2promotes tumor progression by inducing myeloid-derived suppressor cells.Cancer Research 67, 4507–4513.

Soerjomataram, I., Lortet-Tieulent, J., Parkin, D.M., Ferlay, J., Mathers, C., Forman, D.,Bray, F., 2012. Global burden of cancer in 2008: A systematic analysis ofdisability-adjusted life-years in 12 world regions. The Lancet 380, 1840–1850.

Solinas, G., Germano, G., Mantovani, A., Allavena, P., 2009. Tumor-associatedmacrophages (TAM) as major players of the cancer-related inflammation. Journalof Leukocyte Biology 86, 1065–1073.

Sorenmo, K.U., Goldschmidt, M.H., Shofer, F.S., Goldkamp, C., Ferracone, J., 2004.Evaluation of cyclooxygenase-1 and cyclooxygenase-2 expression and the effectof cyclooxygenase inhibitors in canine prostatic carcinoma. Veterinary andComparative Oncology 2, 13–23.

Swierczak, A., Cook, A.D., Lenzo, J.C., Restall, C.M., Doherty, J.P., Anderson, R.L.,Hamilton, J.A., 2014. The promotion of breast cancer metastasis caused byinhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor.Cancer Immunology Research 2, 765–776.

Talmadge, J.E., Donkor, M., Scholar, E., 2007. Inflammatory cell infiltration of tumors:Jekyll or Hyde. Cancer and Metastasis Reviews 26, 373–400.

Taulescu, M.A., Valentine, B.A., Amorim, I., Gartner, F., Dumitrascu, D.L., Gal, A.F.,Sevastre, B., Catoi, C., 2014. Histopathological features of canine spontaneousnon-neoplastic gastric polyps – a retrospective study of 15 cases. Histology andHistopathology 29, 65–75.

Thun, M.J., Henley, S.J., Patrono, C., 2002. Nonsteroidal anti-inflammatory drugs asanticancer agents: Mechanistic, pharmacologic, and clinical issues. Journal of theNational Cancer Institute 94, 252–266.

Tsuyada, A., Chow, A., Wu, J., Somlo, G., Chu, P., Loera, S., Luu, T., Li, A.X., Wu, X., Ye,W., et al., 2012. CCL2 mediates cross-talk between cancer cells and stromalfibroblasts that regulates breast cancer stem cells. Cancer Research 72, 2768–2779.

Ueno, T., Toi, M., Saji, H., Muta, M., Bando, H., Kuroi, K., Koike, M., Inadera, H.,Matsushima, K., 2000. Significance of macrophage chemoattractant protein-1 inmacrophage recruitment, angiogenesis, and survival in human breast cancer.Clinical Cancer Research 6, 3282–3289.

Vakkila, J., Lotze, M.T., 2004. Inflammation and necrosis promote tumour growth.Nature Reviews Immunology 4, 641–648.

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

13T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■

Vazquez-Martin, A., Colomer, R., Menendez, J.A., 2007. Protein array technology todetect HER2 (erbB-2)-induced ‘cytokine signature’ in breast cancer. EuropeanJournal of Cancer 43, 1117–1124.

Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M., Stockinger, B., 2006. TGFβ inthe context of an inflammatory cytokine milieu supports de novo differentiationof IL-17-producing T cells. Immunity 24, 179–189.

Vinothini, G., Balachandran, C., Nagini, S., 2009. Evaluation of molecular markers incanine mammary tumors: Correlation with histological grading. OncologyResearch 18, 193–201.

Waris, G., Ahsan, H., 2006. Reactive oxygen species: Role in the development of cancerand various chronic conditions. Journal of Carcinogenesis 5, 14.

Waugh, D.J., Wilson, C., 2008. The interleukin-8 pathway in cancer. Clinical CancerResearch 14, 6735–6741.

Wolf, M.J., Hoos, A., Bauer, J., Boettcher, S., Knust, M., Weber, A., Simonavicius, N.,Schneider, C., Lang, M., Sturzl, M., et al., 2012. Endothelial CCR2 signaling inducedby colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPKpathway. Cancer Cell 22, 91–105.

Wolff, C., Malinowsky, K., Berg, D., Schragner, K., Schuster, T., Walch, A., Bronger,H., Hofler, H., Becker, K.F., 2011. Signalling networks associated with urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in breast cancertissues: New insights from protein microarray analysis. Journal of Pathology223, 54–63.

Wu, X., Cai, M., Ji, F., Lou, L.M., 2014. The impact of COX-2 on invasion of osteosarcomacell and its mechanism of regulation. Cancer Cell International 14, 27.

Wyckoff, J.B., Wang, Y., Lin, E.Y., Li, J.F., Goswami, S., Stanley, E.R., Segall, J.E., Pollard,J.W., Condeelis, J., 2007. Direct visualization of macrophage-assisted tumor cellintravasation in mammary tumors. Cancer Research 67, 2649–2656.

Xiong, H., Zhang, Z.G., Tian, X.Q., Sun, D.F., Liang, Q.C., Zhang, Y.J., Lu, R., Chen, Y.X.,Fang, J.Y., 2008. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cyclearrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 10,287–297.

Yao, X., Huang, J., Zhong, H., Shen, N., Faggioni, R., Fung, M., Yao, Y., 2014. Targetinginterleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacologyand Therapeutics 141, 125–139.

Zaidi, M.R., Merlino, G., 2011. The two faces of interferon-γ in cancer. Clinical CancerResearch 17, 6118–6124.

Zarogoulidis, P., Yarmus, L., Darwiche, K., Walter, R., Huang, H., Li, Z., Zaric, B., Tsakiridis,K., Zarogoulidis, K., 2013. Interleukin-6 cytokine: A multifunctional glycoproteinfor cancer. Immunome Research 9, 16535.

Zeisberger, S.M., Odermatt, B., Marty, C., Zehnder-Fjallman, A.H., Ballmer-Hofer,K., Schwendener, R.A., 2006. Clodronate-liposome-mediated depletion oftumour-associated macrophages: A new and highly effective antiangiogenictherapy approach. British Journal of Cancer 95, 272–281.

Zhang, J., Patel, L., Pienta, K.J., 2010. Targeting chemokine (C-C motif) ligand 2 (CCL2)as an example of translation of cancer molecular biology to the clinic. Progressin Molecular Biology and Translational Science 95, 31–53.

Zhong, H., Gutkin, D.W., Han, B., Ma, Y., Keskinov, A.A., Shurin, M.R., Shurin, G.V., 2014.Origin and pharmacological modulation of tumor-associated regulatory dendriticcells. International Journal of Cancer 134, 2633–2645.

Zubair, A., Frieri, M., 2013. Role of nuclear factor-κB in breast and colorectal cancer.Current Allergy and Asthma Reports 13, 44–49.

Zuccari, D.A., Castro, R., Gelaleti, G.B., Mancini, U.M., 2011. Interleukin-8 expressionassociated with canine mammary tumors. Genetics and Molecular Research 10,1522–1532.

ARTICLE IN PRESS

Please cite this article in press as: T.P. Raposo, B.C.B. Beirão, L.Y. Pang, F.L. Queiroga, D.J. Argyle, Inflammation and cancer: Till death tears them apart, The Veterinary Journal(2015), doi: 10.1016/j.tvjl.2015.04.015

14 T.P. Raposo et al./The Veterinary Journal ■■ (2015) ■■–■■