Molecular Pathways

Regulation of Cancer Stem Cells by Cytokine Networks:Attacking Cancer's Inflammatory Roots

Hasan Korkaya, Suling Liu, and Max S. Wicha

AbstractThere is substantial evidence that many human cancers are driven by a subpopulation of cells

that display stem cell properties. These cancer stem cells (CSC) may also contribute to metastasis

and treatment resistance. Furthermore, just as normal stem cells are regulated by their micro-

environment, or niche, CSCs interact with and in turn are regulated by cells in the tumor micro-

environment. These interactions involve inflammatory cytokines, such as interleukin (IL)-1, IL-6, and

IL-8, which in turn activate Stat3/NF-kB pathways in both tumor and stromal cells. Activation of these

pathways stimulates further cytokine production, generating positive feedback loops that in turn drive

CSC self-renewal. These cytokine loops and the pathways they regulate resemble those activated

during chronic inflammation and wound healing, and may contribute to the known link between

inflammation and cancer. Inhibitors of these cytokines and their receptors have been developed as

anti-inflammatory agents. By blocking signals from the tumor microenvironment, these agents

have the potential to target CSCs. Future clinical trials using these compounds will be needed

to determine whether targeting the CSC population has clinical benefit. Clin Cancer Res; 17(19);

6125–9. �2011 AACR.

Background

Cancer stem cellsThere is increasing evidence that many human tumors

display a hierarchical organization in which a subset oftumor cells with stem cell properties drives tumor growthand metastasis (1, 2). Furthermore, by virtue of theirrelative resistance to radiation and chemotherapy, thesecells may contribute to treatment resistance and relapseafter therapy. If this is the case, then more effectivetreatments will require effective targeting of this cellpopulation. As is the case with their normal counterparts,cancer stem cells (CSC) are regulated by intrinsic signalsas well as extrinsic signals originating in the tumormicroenvironment (3–5). In the case of CSCs, epigeneticas well as genetic changes that occur during carcinogen-esis result in dysregulation of self-renewal pathways.Stem cell regulatory pathways that are frequently dysreg-ulated in tumors include the Notch, Hedgehog, Wnt,phosphoinositide 3-kinase (PI3K) NF-kB, and Jak/Stat3pathways (6–10). These pathways may be activated viamutation of key regulatory elements. In addition, path-way dysregulation may result from altered interactions

between these cells and the tumor microenvironment(11). Emerging evidence suggests that tumors and theirmicroenvironment coevolve during tumor progression(3). Bidirectional paracrine signals coordinately regulatetumorigenic cell populations, including CSCs (7, 12–14).Tumorigenic cells in turn produce factors that attract andregulate a diverse variety of cell types that constitute thetumor microenvironment (12, 14). Inflammatory cyto-kines, such as interleukin (IL)-1, IL-6, and IL-8, play apivotal role in mediating the interaction between CSCsand the microenvironment. Of interest, many of thepathways that are activated during tumor formationresemble those that mediate normal wound healing.Here, we review the links between inflammation andCSCs, with an emphasis on the cytokine networks andsignaling pathways that link these processes. These path-ways provide potential targets for the development ofnovel strategies to target CSC populations.

Inflammation and cancer stem cellsConsiderable clinical evidence points to links between

inflammatory states and cancer development. Epidemiolo-gic studies have demonstrated associations between ulcera-tive colitis, hepatitis C, and chronic pancreatitis and thedevelopment of cancers of the colon, liver, and pancreas,respectively. Levels of chronic inflammation as assessed byserumC-reactiveproteinorb-amyloidare correlatedwith therisk of breast cancer recurrence after primary therapy (15).The development of chronic inflammation has been asso-ciated with the production of the cytokines IL-1b, IL-6, andIL-8 by a variety of inflammatory cells. Of interest, genetic

Authors' Affiliation: Comprehensive Cancer Center, University of Michi-gan, Ann Arbor, Michigan

Corresponding Author: Max S. Wicha, Comprehensive Cancer Center,University of Michigan, 6303 CGCSPC 5942, Ann Arbor, MI 48109. Phone:734-936-1831; Fax: 734-615-3947; E-mail: mwicha@med.umich.edu

doi: 10.1158/1078-0432.CCR-10-2743

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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polymorphism in genes encoding these cytokines predis-poses affected individuals to cancer (16). Furthermore, theStat3/NF-kB pathway plays a critical role in inducing andmaintaining a procarcinogenic inflammatorymicroenviron-ment at the initiation of malignant transformation andtumor progression (17–19). These inflammatory cytokines,including IL-1, IL-6, and IL-8, may influence tumor growthby regulating CSC populations.

Interleukin-1The IL-1 family consists of IL-1a, IL-1b, and the antago-

nist IL-1Ra. These receptors bind IL-1, which is producedin response to infection or tissue injury, resulting in activa-tion of NF-kB and downstream targets IL-6 and IL-8. Localproduction of IL-1 by tumor-associated macrophagespromotes angiogenesis, tumor growth, and metastasis,

whereas blocking the IL-1 receptor inhibits these processesin mouse models (20, 21). Elevated levels of IL-1 expres-sion in cancer patients are correlated with advanced meta-static disease (22, 23). Furthermore, gene expressionprofiling shows higher IL-1 expression in breast CSCscompared with their more differentiated counterparts (7).

Interleukin-6IL-6 is a pleiotropic cytokine that is secreted by a wide

range of cells and plays a crucial role in immunoregulation.Elevated levels of IL-6 have been associated with chronicinflammatory states, sepsis, hypertension, obesity, insulinresistance, and poor survival in cancer patients, increasingtheir risks for developing malignancies (24, 25). In cancerpatients, high levels of IL-6 are associated with poor patientoutcome, and in preclinical models, IL-6 has been shown

© 2011 American Association for Cancer Research

Immune cells Tumor microenvironment

IL-1

IL-1R

IL-6

IL-6R

gp-130

α-IL-6R Ab

CXCR1/2IL-8

IL-8

IL-6

PI3K

Akt

PTEN

IκB

IκBp50

p50 Target genes

Proteosome

NF-κBinhibitors

Can

cer

stem

cel

l

RelA

RelA

Lin28 Let-7

CYLD

Stat3 inhibitors

P

Stat3 miR-21

Akt inhibitors

CXCR1/2 blockers

Figure 1. Regulation of CSCs by inflammatory cytokine networks. Binding of the IL-6–IL-6R complex to gp130, and IL-8 to CXCR1/2 activates the NF-kBpathway via Stat3 and Akt signaling. IL-6 and IL-8 production by NF-kB generates a positive feedback loop that maintains constitutive pathwayactivation. Inhibition of pathway components by pharmacologic agents is illustrated. Ab, antibody.

Korkaya et al.

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to promote tumorigenesis, angiogenesis, and metastasis(26, 27). IL-6 has been shown to be a direct regulator ofbreast CSC self-renewal (13), a process that is mediated bythe IL-6 receptor/GP130 complex through activation ofStat3 (Fig. 1). In inflammatory cells, IL-6–mediated Stat3signaling selectively induces a procarcinogenic, tumori-genic microenvironment (28). Stat3 activation in turnleads to transcriptional activation of NF-kB in inflamma-tory cells that secretes additional IL-6 and IL-8 acting ontumor cells. Thus, these cytokines generate a positive feed-back loop between immune cells and tumor cells thatfurther stimulates the tumor stem cell components, accel-erating metastasis and therapeutic resistance (Fig. 1). Usingmouse xenografts, we recently demonstrated that bonemarrow mesenchymal stem cells are recruited to sites ofgrowing breast cancers by gradients of IL-6 (12). Further-more, IL-6 is a key component of a positive feedback loopinvolving these bone marrow mesenchymal stem cells andbreast CSCs (12). Sethi and colleagues (29) recentlydemonstrated that IL-6–meditated Jagged1-Notch1 pro-motes breast cancer metastasis to bone. Because Notch isalso a stem cell regulator, this suggests that IL-6 mayregulate stem cells through multiple pathways. These stu-dies identify IL-6 and its receptor as attractive therapeutictargets.

Interleukin-8IL-8 is a proinflammatory cytokine that functions in

different biologic processes, such as neutrophil chemotaxisand angiogenesis. It activates multiple intracellular signal-ing pathways by binding its receptors, CXCR1 and CXCR2.Within the tumor microenvironment, a diverse variety ofcells, including mesenchymal cells, macrophages, andimmune cells, secrete IL-8 (30). Serum IL-8 levels inpatients with cancer have been associated with aggressivecancer behavior and poor prognosis (31, 32). Using geneexpression profiling, we previously identified the IL-8receptor CXCR1 as being highly expressed on breast CSCs(33). Recombinant IL-8 increased breast CSC self-renewaland tumor growth. In contrast, blocking this receptor inmouse xenografts with repertaxin, a small-molecule inhi-bitor, significantly reduced the breast CSC population,leading to decreased tumorigenicity and metastasis.

NF-kB pathwayThe NF-kB family is composed of 5 related transcription

factors: p50, p52, RelA (p65), c-Rel, and RelB (34, 35). Inresting cells, NF-kB proteins are predominantly foundin the cytoplasm, where they are associated with the IkBfamily of proteins (Fig. 1). Activation of NF-kB by diversesignals results in ubiquitin ligase-dependent degradation ofIkB and nuclear translocation of NF-kB protein complexes.A number of cytokines, including IL-6 and IL-8, are regu-lated by NF-kB. In addition, a positive feedback loop wasrecently shown tomaintain a chronic inflammatory state intumor cells. Of interest, this loop involves the microRNAlet7, as well as Lin28, a factor involved in embryonic stemcell self-renewal (7). This feedback loop is maintained by

IL-6–mediated Stat3 activation, which in turn activates NF-kB, affecting Lin28 and let7 (Fig. 1). The specific role of IL-6in maintaining this inflammatory loop in breast CSCs wasrecently demonstrated (7, 10). NF-kB may play an impor-tant role in normal breast physiology, as well as in carci-nogenesis. In an HER2-neu model of mammarycarcinogenesis, suppression of NF-kB in mammary epithe-lium reduced the mammary stem cell compartment, result-ing in delayed onset of HER2-neu–induced tumors (36).NF-kB has also been implicated in the regulation of mousemammary stem cells during pregnancy. Elevated levels ofprogesterone during pregnancy induce RANK ligand(RANKL) in differentiated breast epithelial cells. In turn,RANKL stimulates breast stem cell self-renewal via activa-tion of NF-kB in these cells (37, 38). The increased inci-dence of aggressive breast cancers associated withpregnancy (39) may result from activation of similar path-ways in breast CSCs (37, 38).

Clinical–Translational Advances

Solid tumors are composed of heterogeneous cell popu-lations that interact in complex networks. As is the case indeveloping organs, tumor cells interact with and in turn areregulated by these components in the microenvironment.Metastatic tumor cells also recreate complex cellular micro-environments at metastatic sites. More than 120 years ago,Paget proposed the "seed and soil" hypothesis of tumormetastasis (40). Reframed in a modern context, the "seeds"are the CSCs and the "soil" is the rich microenvironment,which is composed of diverse cell types that interact withtumor cells via cytokine networks. These networks regulateCSCs and their progeny, which form the tumor bulk.Elucidation of these pathways may provide new targetsfor therapeutic development. Examples of such pathwaysinclude the cytokines IL-6 and IL-8 and their receptors IL-6R and CXCR1. Blockade of these cytokine pathways reduc-ed breast CSCs in preclinical models (33). Clinical trialsusing IL-6–blocking antibodies have been initiated forthe treatment of multiple myeloma, and early results areencouraging (41). Furthermore, an anti–IL-6R antibody,tocilizumab, has been approved for the treatment of arthri-tis (42) and has little clinical toxicity. A small-moleculeCXCR1 inhibitor, repertaxin, was developed to block rejec-tion in renal transplant patients, and early results fromclinical trials suggest that it is well tolerated. Phase I clinicaltrials combining this cytokine receptor/inhibitor withchemotherapy are being planned. NF-kB also representsan attractive therapeutic target. Preclinical studies suggestthat the NF-kB inhibitor parthenolide is able to targetleukemic stem cells, and early-stage clinical trials for thetreatment of leukemia with this agent are in progress.Together, these trials will determine the feasibility of tar-geting CSCs by blocking interaction of these cells with thetumor microenvironment.

The CSC model has important implications for clinicaltrial design. Currently, tumor response rate is determinedby tumor size as described by Response Evaluation Criteria

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in Solid Tumors (RECIST). For many tumors, regressiondoes not correlate with increased patient survival (43–45). Because CSCs may constitute only a minor fractionof a tumor, agents that target this population may notproduce tumor regression. In fact, stem cell–targetingagents would be expected to have more dramatic effectsin the adjuvant setting than in advanced-tumor settings(46). This suggests that in advanced disease, it will benecessary to combine CSC-targeting agents with debulk-ing approaches such as chemotherapy or radiation ther-apy. The time-to-tumor progression may prove a moreuseful clinical endpoint than tumor regression in suchstudies. However, because the non–stem-cell fraction oftumors may still retain a proliferative capacity, it isimportant to use accurate criteria to define tumor pro-gression to ensure that patients are not removed fromtreatment prematurely. The evaluation of CSC biomar-kers, such as CD44, CD133, and aldehyde dehydrogen-ase-1, in serial biopsies may provide a tool to assess theefficacy of CSC-targeting agents (47–49). Circulatingtumor cells may also provide a valuable source of CSCpopulations for biomarker analysis. These assays willneed to be able to capture circulating CSCs, which maynot express antigens that are currently used, such as Ep-CAM. A neoadjuvant trial design may prove to be parti-

cularly useful for assessing the effects of CSC-targetingagents, because acquiring tissue before and after treat-ment enables one to assess the efficacy of CSC targeting.In addition, the effects of these agents on increasing thecomplete pathologic response rate, an acceptedclinical endpoint, can be readily assessed. Ultimately,randomized trials will be required to determine whethersuccessful targeting of CSCs improves patient outcome.

Disclosure of Potential Conflicts of Interest

Max S. Wicha has financial holdings in and is a scientific advisor forOncoMed Pharmaceuticals. He is a scientific advisor for Pfizer, Merck, andOrtho-Clinical Diagnostics, and he receives research support from DompePharmaceuticals.

Acknowledgments

We thank Shawn G. Clouthier for a critical review of this manuscript.

Grant Support

National Institutes of Health (CA129765 and CA101860), American Associa-tion for Cancer Research (SU2C Dream Team Award), Breast Cancer ResearchFoundation, and Taubman Research Institute.

Received March 30, 2011; revised May 24, 2011; accepted May 25, 2011;published OnlineFirst June 17, 2011.

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