Targeting Inflammatory Pathways for Prevention andTherapy ofCancer: Short-Term Friend, Long-Term FoeBharat B. Aggarwal, R.V. Vijayalekshmi, and Bokyung Sung

Abstract Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and high-calorie diet have been recognized as major risk factors for the most common types of cancer.All these risk factors are linked to cancer through inflammation. Although acute inflammationthat persists for short-term mediates host defense against infections, chronic inflammation thatlasts for long term can predispose the host to various chronic illnesses, including cancer. Linkagebetween cancer and inflammation is indicated by numerous lines of evidence; first, transcriptionfactors nuclear factor-nB (NF-nB) and signal transducers and activators of transcription 3(STAT3), two major pathways for inflammation, are activated by most cancer risk factors;second, an inflammatory condition precedes most cancers; third, NF-nB and STAT3 are cons-titutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumorsactivate NF-nB; fifth, chemotherapeutic agents and g-irradiation activate NF-nB and lead tochemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival,proliferation, invasion, angiogenesis, andmetastasis are regulated by NF-nBand STAT3; seventh,suppression of NF-nB and STAT3 inhibits the proliferation and invasion of tumors; and eighth,most chemopreventive agents mediate their effects through inhibition of NF-nB and STAT3activation pathways. Thus, suppression of these proinflammatory pathways may provide oppor-tunities for both prevention and treatment of cancer.

Cancer is now generally believed to be a preventable disease.Only 5% to 10% of all cancers are caused by inheritance ofmutated genes and somatic mutations, whereas the remain-ing 90% to 95% has been linked to lifestyle factors andenvironment (1). Almost 30% of all cancers have beenattributed to tobacco smoke,1 35% to diet (2), 14% to 20%to obesity (3), 18% to infections (4), and 7% to radiation andenvironmental pollutants (5). The underlying mechanisms bywhich these risk factors induce cancer are becoming increas-ingly evident. One process that seems to be common to allthese risk factors is inflammation.The great German pathologist Rudolph Virchow (1821-

1902) once remarked: ‘‘that chronic irritation which is mani-fested by a chronic inflammation is a key promoter of cancer.’’Inflammation (derived from Latin word ‘‘inflammatio ,’’ to seton fire), a complex biological response to harmful stimuli, wascharacterized by the first century Roman physician Cornelius

Celsus as that which consists of heat (calor), redness (rubor),pain (dolor), and swelling (tumor). There are two stages ofinflammation, acute and chronic. Acute inflammation is aninitial stage of inflammation (innate immunity) mediatedthrough activation of the immune system; it helps the bodyward off infections, it lasts for short period and generally isregarded as therapeutic inflammation. If the inflammationpersists for a long period of time, however, the second stage ofinflammation, i.e., chronic inflammation sets in (6). Althoughthis chronic inflammation has been now linked with mostchronic illnesses, including cancer, cardiovascular diseases,diabetes, obesity, pulmonary diseases, and neurologic diseases(7), the current review focuses on the role of inflammatorypathways in tumorigenesis. Nuclear factor-nB (NF-nB) andsignal transducers and activators of transcription 3 (STAT3) aretwo most important transcription factors in inflammatorypathways that play major roles in tumorigenesis and thuscan be considered targets for prevention and therapy of cancer(6, 8).NF-nB was discovered in 1986 as a nuclear factor that binds

to the enhancer region of the nB chain of immunoglobulin in Bcells. It has been shown since, however, to be a ubiquitoustranscription factor present in all cell types. In its resting stage,this factor resides in the cytoplasm as a heterotrimer consistingof p50, p65, and InBa (Fig. 1). On activation, the InBa protein,an inhibitor of NF-nB, undergoes phosphorylation, ubiquiti-nation, and degradation. p50 and p65 are then released to be

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Authors’Affiliation: Cytokine Research Laboratory, Department of ExperimentalTherapeutics,The University ofTexasM.D. Anderson Cancer Center, Houston,TexasReceived1/18/08; revised 8/4/08; accepted 8/11/08.Grant support: B.B. Aggarwal is the Ransom Horne, Jr. Professor of CancerResearch. This work was supported by a grant from the Clayton Foundation forResearch (B.B. Aggarwal).Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory,Department of Experimental Therapeutics,The University of Texas M. D. AndersonCancer Center, 1515 Holcombe Boulevard, Houston,TX 77030. Phone: 713-794-1817; Fax: 713-745-6339; E-mail: aggarwal@mdanderson.org.

F2009 American Association for Cancer Research.doi:10.1158/1078-0432.CCR-08-0149 1http://www.dietandcancerreport.org/?p=ER

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translocated to the nucleus, bind specific DNA sequencespresent in the promoters of various genes, and initiatetranscription. The kinase that causes the phosphorylation ofInBa is called InBa kinase or IKK. Whereas IKKh mediatesthe classic/canonical NF-nB activation pathway, IKKa mediatesthe noncanonical pathway. What causes the activation of IKKis not well-understood. More than a dozen different kinases

have been described that can activate IKK including AKT,mitogen-activated protein/extracellular signal-regulated kinasekinase kinase 1 (MEKK1), MEKK3, transforming growthfactor–activating kinase 1, NF-nB–activating kinase, NF-nB–inducing kinase, protein kinase C, and the double-strandedRNA-dependent protein kinase PKR. Various gene productsthat have been shown to mediate inflammation, cell survival,

Fig. 1. Association of NF-nB signaling pathway with tumorigenesis. 5-LOX, 5-lipooxygenase; bFGF, basic fibroblast growth factor; cFLIP, cellular caspase-8 (FLICE)-likeinhibitory protein; cIAP1, inhibitor of apoptosis protein; COX-2, cyclooxygenase-2; CXCR4, CXC chemokine receptor-4; EGFR, EGF receptor; ELAM-1, endothelial cellleukocyte adhesion molecule-1; H. pylori, Helicobacter pylori ; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesionmolecule-1; IjBa, inhibitor of nBa; IKK, InB kinase;MMP-9, matrixmetalloproteinase-9; PDGF, platelet-derived growth factors; PTK, protein tyrosine kinase;RANKL, receptoractivator for nuclear factor nB ligand; S. typhi, Salmonella typhi ;TAK1,TGF-activated kinase-1;TNFR,TNF receptor; uPA, urokinase-type plasminogen activator;VCAM-1,vascular cell adhesion molecule-1;VEGF, vascular endothelial growth factor; XIAP, X-linked Inhibitor of apoptosis protein.

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cell proliferation, invasion, angiogenesis, and metastasis areregulated by NF-nB. Similarly, most agents that promoteinflammation and proliferation activate NF-nB. These includeendotoxin, carcinogens (such as cigarette smoke), radiation,chemotherapeutic agents, hyperglycemia, tumor promoters,inflammatory cytokines [e.g., tumor necrosis factor (TNF) andinterleukin (IL)-1] and growth factors [e.g., epidermal growthfactor (EGF); ref. 9].STAT3 is another transcription factor that is normally present

in the cytoplasm of most cells. In response to certaininflammatory stimuli (e.g., IL-6) and growth factors (e.g.,EGF), STAT3 undergoes sequential tyrosine phosphorylation,homodimerization, nuclear translocation, DNA binding, andgene transcription. Several protein kinases that cause specificphosphorylation of STAT3 have been identified, includingJanus-activated kinase 1, 2, and 3. Similarly, protein phospha-tases that cause the dephosphorylation of STAT3 also havebeen identified. Gene products linked with survival (e.g., Bcl-xL), proliferation (e.g., cyclin D1), and angiogenesis (e.g.,vascular endothelial growth factor) are regulated by STAT3activation (8).

Clinical-Translational Advances

Most carcinogens activate NF-kB and STAT3 pathways. Mostcarcinogens, including cigarette smoke (10), polycyclic hydro-carbons (11), asbestos (12), alcohol (13), sun light (14), andUV light (15), have been shown to activate the proinflamma-tory NF-nB pathway. Almost all infectious agents linked withcancer activate NF-nB. For instance, human papillomavirus(16), HIV (17), human herpes virus (18), EBV (19), hepatitis Bvirus (20), hepatitis C virus (21), and Helicobacter pylori (22)have been shown to activate NF-nB. The roles of humanpapillomavirus in cervical cancer, human herpes virus inlymphoma, hepatitis B virus and hepatitis C virus in hepatocel-lular carcinoma,Helicobacter pylori in gastric cancer and HIV, andEBV in leukemia, are well-documented. Hyperglycemia associ-ated with diabetes and obesity, a risk factor for various cancers,has been shown to mediate NF-nB activation (23). Moreover,most growth factors (such as EGF) and growth factor receptorssuch as EGF receptor and HER2 have been shown to mediateNF-nB activation (24, 25). TNF, the proinflammatory cytokinethat has been linked with survival, proliferation, invasion, andmetastasis of tumors, is one of the most prominent activators ofNF-nB (26).How all these diverse agents activate NF-nB is not fully

understood (Fig. 1). That cigarette smoke and EGF activate NF-nB through a mechanism different from that of TNF has beenshown in our laboratory (27, 28). Whereas TNF-induced NF-nBactivation was found to be IKK dependent, for example, EGFactivated NF-nB through an IKK-independent mechanism (28).Similarly, the mechanism of NF-nB activation by UV, the majorrisk factor for melanoma, has been shown to be different fromthat of TNF (29). Most solid tumors exhibit hypoxic and acidicconditions in their core; both of these conditions can lead toNF-nB activation (30). Proinflammatory cytokine IL-6, whoseexpression is regulated by NF-nB, is a potent activator of theSTAT3 pathway (31). STAT3 is also activated by EGF and othergrowth factors linked to tumorigenesis (32). Although NF-nBand STAT3 activation by most agents is transitory, however,

long-term exposure is likely to make it irreversible. These linesof evidence strongly support the hypothesis that carcinogen-induced NF-nB activation could lead to tumorigenesis.Inflammation precedes most cancers. The suffix ‘‘itis’’ is used

typically to denote inflammation. Bronchitis, colitis, cervicitis,gastritis, and hepatitis, for example, reflect inflammation of thebronchus, colon, cervix, stomach, and liver, respectively. Itseems that most cancers, especially solid tumors, are precededby inflammation of a given organ. For instance, people whosmoke cigarette develop bronchitis, and 15% to 20% of thesepeople develop lung cancer (33). Similarly, people who havecolitis are at high risk of developing colon cancer (34).Infection with Helicobacter pylori can induce gastritis, which inits chronic form can lead to gastric cancer (35).Proinflammatory stimuli such as TNF, IL-1, IL-6, cyclo-

oxygenase-2, and 5-lipo-oxygenase, all regulated by the NF-nBpathway, have been shown to be expressed in bronchitis, colitis,cervicitis, gastritis, or hepatitis. Overexpression of cyclooxyge-nase-2, for example, has been shown in colitis, bronchitis, andgastritis (36). We have recently shown that TNF is overexpressedin head and neck squamous cell carcinoma and mediates tumorcell proliferation (37). Similarly, TNF expression and its pro-liferative role have been shown in mantle cell lymphoma (38),acute myeloid leukemia (39), cutaneous T-cell lymphoma (40),and glioblastoma (41). IL-6, whose expression is regulated byNF-nB, has been shown to induce proliferation of multiplemyeloma cells through activation of the STAT3 pathway (42).Inflammatory cells that express activated NF-nB and secrete

inflammatory cytokines have been shown to contribute totumor initiation and progression (43). For instance, inhibitionof TNF production by nonparenchymal cells (Kupffer andendothelial cells) prevented NF-nB activation in hepatocytesand in early tumors; and reduced tumor multiplicity (44).Greten et al. (45) reported that deleting IKKh in myeloid cellscaused suppression of NF-nB activation, diminished expressionof inflammatory cytokines, and thus leading to a significantdecrease in tumor size.NF-kB and STAT3 are constitutively activated in most tumor

cells. In a majority of tumor cell lines, both solid andhematologic tumors, NF-nB has been shown to be constitu-tively active (46). What causes the constitutive activation ofNF-nB in these tumor cells is not fully understood. Manydifferent mechanisms have been described, including over-expression of growth factor receptors, mutation of InBa suchthat it cannot bind to NF-nB, constitutive activation of ras pro-tein, high proteolytic activity directed to InBa, and autocrinesecretion of inflammatory cytokines. In most of these tumorcells, constitutive activation of NF-nB is responsible forproliferation, because inhibition of NF-nB leads to abrogationof proliferation (47). Constitutive activation also has beenlinked to chemoresistance and radioresistance (48). Constitu-tive activation of STAT3 has been reported in various tumor celllines (8) and is known to mediate proliferation of these cells.Constitutive activation of NF-nB and STAT3 is encountered in

samples from cancer patients (8, 48). We found that cons-titutive activation of NF-nB and STAT3 in CD134+ cells frompatients with multiple myeloma (49). Similarly, we showedconstitutive activation of NF-nB in samples from patients withlung cancer (50) and pancreatic cancer (51).Organ-specific conditional knock-in and knockout of the

inflammatory intermediates promote cancer. Using mice bearing

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mutations in the genes coding for the IKKh and IKKa catalyticsubunits, Karin and his colleagues (52–54) examined the roleof the NF-nB pathway in tumorigenesis. They found that micelacking IKKh only in hepatocytes or hematopoietic-derivedKupffer cells showed a marked increase in hepatocarcinogenesisinduced by diethylnitrosamine (53). Interestingly, althoughtumorigenic function of IKKh was found to be mediated viaNF-nB, the metastatic function of IKKa was found to beindependent of NF-nB (54). Moreover, they showed thatprocesses that occur within inflammatory cells are essentialfor cancer development and progression (53).To determine the role of NF-nB in inflammation-induced

tumor growth, Luo et al. (52) used an experimental murinecancer metastasis model in which a colon adenocarcinoma cellline metastasizes to the lungs when stimulated by lipopolysac-charide. They found that endotoxin-induced metastatic growthresponse depends on TNF-a production by host hematopoieticcells, leading to NF-nB activation in tumor cells. Inhibition ofNF-nB in colon led to tumor regression. The latter depends onTRAIL receptor induction in NF-nB–deficient cancer cells.These findings support the role of inflammatory pathways intumor development.Most genes linked with tumorigenesis are regulated by NF-kB

and STAT3. NF-nB plays a pivotal role, not only in immuneresponse and inflammatory reaction but also in regulatingexpression of genes involved in characteristic processes leadingto tumorigenesis, such as cell survival, proliferation, invasion,angiogenesis, and metastasis (9).Numerous genes have been described that are regulated by

NF-nB and mediate survival of tumor cells. These include cFLIP,(55) Bcl-xL (56), Bcl-2 (57), XIAP (58), c-IAP1 (59), cIAP-2(59), and survivin (60), all of which negatively regulateapoptosis. Some of the genes that are regulated by NF-nB andare linked with proliferation of tumors include cyclin D1 (61),c-myc (62), and cyclooxygenase-2 (63). Other genes such asmatrix metalloproteinase-9 (64), vascular endothelial growthfactor (65), CXCR4 (66), and TWIST (67), which have beenclosely associated with invasion, angiogenesis, and metastasis,also are regulated by NF-nB. STAT3 is known to regulate theexpression of Bcl-xL (68), Mcl-1 (69), survivin (70), cyclin D1(71), vascular endothelial growth factor (72), and TWIST (73).Most proinflammatory genes that have been linked with car-cinogenesis also are regulated by NF-nB and STAT3, includingTNF (74), RANKL (75), IL-1 (76), IL-6 (77), IL-8 (78, 79), andcell surface adhesion molecules such as intercellular adhesionmolecule-1, ELAM-1, and VCAM-1 (80). Thus genes regulatedby NF-nB and STAT3 are clearly implicated in tumorgenesis.Most chemotherapeutic agents and g-radiation activate NF-kB

and mediate chemoresistance and radioresistance. Several che-motherapeutic agents have been shown to activate NF-nB,including paclitaxel, vinblastine, vincristine, doxorubicin,daunomycin, 5-fluorouracil, cisplatin, and tamoxifen in humanlung cancer, cervical cancer, and in T cells (81–83). Ionizingradiation also has been shown to activate this transcriptionfactor in various tumor cells including human myeloidleukemia cells (84). The mechanism by which chemotherapeu-tic agents activate NF-nB, however, differs from that ofg-radiation. Activation of NF-nB by ionizing radiation inducedtyrosine phosphorylation of InBa, whereas that by chemother-apeutic agents involves serine phosphorylation (85). Activationof NF-nB by these agents has been linked in turn with

chemoresistance and radioresistance (48). Thus suppressionof the NF-nB pathway provides a unique window of opportu-nity to overcome chemoresistance and radioresistance. Activa-tion of the NF-nB pathway by these agents is selective; none ofthem activate the STAT3 pathway.Inhibitors of proinflammatory pathways have therapeutic

potential. Because the NF-nB and STAT3 pathways play acritical role in tumorigenesis and in induction of resistance oftumor cells to currently available therapy, inhibitors of thesepathways have enormous potential. Several inhibitors of NF-nBand STAT3 have been reported (8, 48). Some of these inhibitorsare ‘‘proof of principle’’ type, others are rationally designed, andstill others have been identified from natural products knownto have antiinflammatory activities. For instance, a peptidederived from the phosphorylation domain of p65 can blockNF-nB activation and enhance the effect of chemotherapeuticagents (86). Similarly, proteasome inhibitors that were ratio-nally designed as a NF-nB inhibitor, when combined withchemotherapy, can potentiate its effects in multiple myeloma(87, 88). For instance, Velcade, a proteasome inhibitor, hasbeen shown to suppress the NF-nB activation of multiplemyeloma cells in culture (89). However, there is no data toindicate that Velcade could inhibit NF-nB activation in thepatients. Similarly, thalidomide has been shown to suppressNF-nB activation in cell culture and inhibit cell growth (90).Such data in the patients treated with thalidomide analogues,is lacking.Numerous agents identified from natural sources can block

the NF-nB pathway, including curcumin, resveratrol, ursolicacid, capsaicin, silymarin, guggulsterone, and plumbagin(91–97). Several of these agents also suppress the STAT3pathway (98–103), suggesting that they exhibit multipletargets. In addition to agents from natural products, syntheticand semisynthetic agents also inhibit the NF-nB or STAT3pathway. For example, the semisynthetic compound flavopir-idol has been reported its activity on NF-nB and STAT3suppression. Pharmacologically, these agents have been shownto be quite safe, and thus, they can be used not for justprevention but also therapy. In human clinical trials, curcuminhas been shown to actually down-regulate both the NF-nB andSTAT3 pathways (104). To our knowledge, curcumin is theonly agent among all those tested in patients that has beenshown to down-regulate both the NF-nB and STAT3 pathways(49, 51, 104). By this property, therefore, curcumin has beenshown to have potential in the treatment of human pancreaticcancer (51), familial adenomatous polyposis (105), inflamma-tory bowel disease (Crohn’s disease; ref. 106), irritable boweldisease (107), and other proinflammatory diseases (108) inclinical trials. Further clinical trials are needed to fully realizethe potential of the inflammatory pathways described here inthe treatment of human cancers.

Conclusion

Whether the objective is prevention or therapy of cancer, thetargets are the same. The evidence described here clearly showsthat inflammatory pathways are critical targets in bothprevention and therapy of cancer. Therefore, identification ofagents/drugs that can suppress these pathways has enormouspotential. Most drugs fail because they are monotargeted, toxic,ineffective, and unaffordable by many. Because of cross-talk

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between the pathways, cancers are caused by dysregulation ofmultiple pathways. Thus, agents that can suppress NF-nB, STAT3,and other pathways (e.g., PI3K/AKT, HIF-1) are likely to be moreeffective drugs. Because of their safety and ability to affectmultiple targets, natural products are likely to have a specialplace in the preventive and therapeutic armamentarium forcancer. Although there are plenty of preclinical data to supportsuch claims, only clinical studies can fully validate them.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Kathryn Hale for editorial review of this manuscript and acknowledgesupport from NIH/National Cancer Institute grant1PO1CA1248701A2.

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