Free Radical Biology & Medicine 49 (2010) 1603–1616

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Free Radical Biology & Medicine

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f r e e r a d b i o m e d

Review Article

Oxidative stress, inflammation, and cancer: How are they linked?

Simone Reuter, Subash C. Gupta, Madan M. Chaturvedi, Bharat B. Aggarwal ⁎
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

a r t i c l e i n f o a b s t r a c t

Article history: Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative
Received 25 June 2010 stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer,
Revised 30 August 2010 diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of
Accepted 3 September 2010
transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these
Available online 16 September 2010
transcription factors can lead to the expression of over 500 different genes, including those for growth factors,
Keywords:
inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How
Oxidative stress oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell,
Inflammation tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell
Cancer survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic
Pro-oxidants inflammation, and cancer are closely linked.
Antioxidants © 2010 Elsevier Inc. All rights reserved.
NF-κB
Free radicals

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1604
Inflammatory network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1604
Pro-oxidant network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605
Cellular transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606
Tumor cell survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607
Tumor cell proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607
Tumor cell invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608
Tumor cell angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608
Chemoresistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609
Radioresistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1610
Stem cell survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1610
Stromal cell signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611

Abbreviations: Akt, AKT8 virus oncogene cellular homolog; AP-1, activator protein-1; Cdk, cyclin-dependent kinase; CSC, cancer stem cell; Cu-ZnSOD, copper–zinc superoxide
dismutase; CXCR4, CXC chemokine receptor 4; EC-SOD, extracellular superoxide dismutase; eNOS, endothelial nitric oxide synthase; ERK/MAPK, extracellular signal-regulated
kinase/mitogen-activated protein kinase; FGF, fibroblast growth factor; Flk1/KDR, fetal liver kinase 1/kinase insert domain receptor; GPx, glutathione peroxidase; GSH, glutathione;
HIF-1α, hypoxia-inducible factor-1α; HMOX-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IκBα, inhibitor of κBα; IL, interleukin; iNOS, inducible nitric oxide
synthase; JNK, c-Jun N-terminal kinase; c-Jun, cellular Ju-nanna; Keap1, Kelch-like ECH-associated protein 1; LPS, lipopolysaccharide; MDR, multidrug resistance; MDM2, murine
double minute 2; MKP, mitogen-activated protein kinase phosphatase; MMP, metalloproteinase; Mn-SOD, manganese superoxide dismutase; Myc, avian myeloblastosis virus
oncogene; NF-κB, nuclear factor κB; nNOS, neuronal NOS; Nox, NADPH oxidase; Nrf2, NF-E2 related factor-2; 8-OHdG, 8-hydroxydeoxyguanosine; PGP, P-glycoprotein; PI3K,
phosphoinositide 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor-γ; PTEN, phosphatase and tensin homolog deleted from chromosome 10; Prx, peroxiredoxin; Ras,
rat sarcoma viral oncogene; ROS, reactive oxygen species; RNS, reactive nitrogen species; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription 3; TAM,
tumor-associated macrophages; TGF-β, transforming growth factor-β; TLR, toll-like receptor; TNF, tumor necrosis factor; TSP-1, thrombospondin-1; VEGF-A, vascular endothelial
growth factor-A; Wnt, wint.
⁎ Corresponding author. Fax: +1 713 745 6339.
E-mail address: aggarwal@[Link] (B.B. Aggarwal).

0891-5849/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/[Link].2010.09.006
1604 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616

Introduction ROS are involved in a wide spectrum of diseases, including chronic

inflammation (Table 1), and in a wide variety of cancers (Table 2).
Oxidative stress is defined as an imbalance between production of Chronic inflammation is induced by biological, chemical, and
free radicals and reactive metabolites, so-called oxidants or reactive physical factors and is in turn associated with an increased risk of
oxygen species (ROS), and their elimination by protective mechan- several human cancers [54]. The link between inflammation and
isms, referred to as antioxidants. This imbalance leads to damage of cancer has been suggested by epidemiological and experimental data
important biomolecules and cells, with potential impact on the whole [55,56] and confirmed by anti-inflammatory therapies that show
organism [1]. ROS are products of a normal cellular metabolism and efficacy in cancer prevention and treatment [57]. The fact that
play vital roles in the stimulation of signaling pathways in plant and continuous irritation over long periods of time can lead to cancer had
animal cells in response to changes in intra- and extracellular already been described in the traditional Ayurvedic (meaning “the
environmental conditions [2]. Most ROS are generated in cells by science of long life”) medical system, written as far back as 5000 years
the mitochondrial respiratory chain [3]. During endogenous metabolic ago [58]. Whether this irritation is the same as what Rudolf Virchow
reactions, aerobic cells produce ROS such as superoxide anion (O2−), referred to as inflammation in the 19th century is uncertain [59].
hydrogen peroxide (H2O2), hydroxyl radical (OH•), and organic Virchow first noted that inflammatory cells are present within tumors
peroxides as normal products of the biological reduction of molecular and that tumors arise at sites of chronic inflammation [60]. This
oxygen [4]. The electron transfer to molecular oxygen occurs at the inflammation is now regarded as a “secret killer” for diseases such as
level of the respiratory chain, and the electron transport chains are cancer. For example, inflammatory bowel diseases such as Crohn
located in the membranes of the mitochondria [5,6]. Under hypoxic disease and ulcerative colitis are associated with increased risk of
conditions, the mitochondrial respiratory chain also produces nitric colon adenocarcinoma [61–63], and chronic pancreatitis is related to
oxide (NO), which can generate reactive nitrogen species (RNS) [3]. an increased rate of pancreatic cancer [64].
RNS can further generate other reactive species, e.g., reactive The exact mechanisms by which a wound-healing process turns
aldehydes—malondialdehyde and 4-hydroxynonenal—by inducing into cancer are topics of intense research [57,65], and possible
excessive lipid peroxidation [7]. Proteins and lipids are also significant mechanisms include induction of genomic instability, alterations in
targets for oxidative attack, and modification of these molecules can epigenetic events and subsequent inappropriate gene expression,
increase the risk of mutagenesis [8]. enhanced proliferation of initiated cells, resistance to apoptosis,
Under a sustained environmental stress, ROS are produced over a aggressive tumor neovascularization, invasion through tumor-asso-
long time, and thus significant damage may occur to cell structure and ciated basement membrane, and metastasis [66]. How oxidative stress
functions and may induce somatic mutations and neoplastic trans- modulates these different stages of inflammation-induced carcino-
formation [9,10]. Indeed, cancer initiation and progression have been genesis is the focus of this review.
linked to oxidative stress by increasing DNA mutations or inducing
DNA damage, genome instability, and cell proliferation [11].
The skin, for example, is chronically exposed to both endogenous Inflammatory network
and environmental pro-oxidants because of its interface function
between the body and the environment, and to protect the skin against The sources of inflammation are widespread and include microbial
this overload of oxidant species, it needs a well-organized system of and viral infections; exposure to allergens, radiation, and toxic
both chemical and enzymatic antioxidants [12]. The lungs, which are chemicals; autoimmune and chronic diseases; obesity; consumption
directly exposed to oxygen concentrations higher than in most other of alcohol; tobacco use; and a high-calorie diet [60,67]. In general, the
tissues, are protected against these oxidants by a variety of antioxidant longer the inflammation persists, the higher the risk of cancer. Two
mechanisms [13]. Furthermore, aging, which is considered an impair- stages of inflammation exist, acute and chronic inflammation. Acute
ment of body functions over time, caused by the accumulation of inflammation is an initial stage of inflammation (innate immunity),
molecular damage in DNA, proteins, and lipids, is also characterized by which is mediated through the activation of the immune system. This
an increase in intracellular oxidative stress due to the progressive type of inflammation persists only for a short time and is usually
decrease in intracellular ROS scavenging [14]. Acting to protect the beneficial for the host. If the inflammation lasts for a longer period of
organism against these harmful pro-oxidants is a complex system of time, the second stage of inflammation, or chronic inflammation, sets
enzymatic antioxidants (e.g., superoxide dismutase (SOD), glutathione in and may predispose the host to various chronic illnesses, including
peroxidase (GPx), glutathione reductase, catalase) and nonenzymatic cancer [68]. During inflammation, mast cells and leukocytes are
antioxidants (e.g., glutathione (GSH), vitamins C and D) [15] (Fig. 1). recruited to the site of damage, which leads to a “respiratory burst”

Table 1
A partial list of diseases that have been linked to reactive oxygen species

Disease Reference

Acute respiratory distress syndrome [16]

Aging [17]
Alzheimer [18,19]
Atherosclerosis [20]
Cancer [21–23]
Cardiovascular disease [24,25]
Diabetes [26]
Inflammation [27]
Inflammatory joint disease [28]
Neurological disease [29]
Obesity [30,31]
Parkinson [32,33]
Pulmonary fibrosis [34,35]
Rheumatoid arthritis [36]
Fig. 1. Schematic representation of various activators and inhibitors of reactive oxygen
Vascular disease [37,38]
species production.
 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616 1605

Table 2 Pro-oxidant network

A partial list of cancers that have been linked to reactive oxygen species

Cancer Reference After an inflammatory stimulus, initiation of carcinogenesis medi-

ated by ROS may be direct (oxidation, nitration, halogenation of nuclear
Bladder [39]
Brain tumor [40] DNA, RNA, and lipids) or mediated by the signaling pathways activated
Breast [41] by ROS. With the help of the mitochondrial respiratory chain, aerobic
Cervical [42] organisms are able to attain a far greater energy production efficiency
Gastric (stomach) [43]
compared with anaerobic organisms. However, one disadvantage of
Liver [44]
Lung [45] aerobic respiration is continuous electron leakage to O2 during
Melanoma [46] mitochondrial ATP synthesis. In fact, 1–5% of total oxygen consumed
Multiple myeloma [47] in aerobic metabolism gives rise to O2−, an example of ROS. To protect
Leukemia [48] against this free radical, the main enzyme for its degradation, the
Lymphoma [49]
manganese superoxide dismutase (Mn-SOD), dismutates it into H2O2
Oral [50]
Ovarian [51] and water [73].
Pancreatic [52] H2O2, another example of ROS, may be formed either by
Prostate [10] dismutation from superoxide anion or spontaneously in peroxisomes
Sarcoma [53]
from molecular oxygen [74–76]. Despite its lesser reactivity compared
with other ROS, H2O2 plays an important role in carcinogenesis
due to an increased uptake of oxygen and, thus, an increased release because it is capable of diffusing throughout the mitochondria and
and accumulation of ROS at the site of damage [7,65]. across cell membranes and producing many types of cellular injury
On the other hand, inflammatory cells also produce soluble [74,75]. The main injurious effects of ROS in mammalian cells are,
mediators, such as metabolites of arachidonic acid, cytokines, and however, mediated by •OH. It has a very unstable electron structure
chemokines, which act by further recruiting inflammatory cells to the and is therefore unable to diffuse more than one or two molecular
site of damage and producing more reactive species. These key diameters before it reacts in practice with any cellular component
mediators can activate signal transduction cascades as well as [76,77]. The majority of •OH in vivo is produced in the presence of
inducing changes in transcription factors, such as nuclear factor κB reduced transition metals (ions of Fe, Cu, Co, or Ni), mainly via the
(NF-κB), signal transducer and activator of transcription 3 (STAT3), Fenton reaction when Fe2+ contacts H2O2. The •OH-derived DNA
hypoxia-inducible factor-1α (HIF-1α), activator protein-1 (AP-1), damage includes the generation of 8-hydroxyguanosine, the hydro-
nuclear factor of activated T cells, and NF-E2 related factor-2 (Nrf2), lysis product of which is 8-hydroxydeoxyguanosine (8-OHdG). 8-
which mediate immediate cellular stress responses (Fig. 2). Induction OHdG is the most widely used fingerprint of radical attack on DNA
of cyclo-oxygenase-2 and inducible nitric oxide synthase (iNOS), [77,78]. 8-OHdG has been strongly implicated in carcinogenesis
aberrant expression of inflammatory cytokines (tumor necrosis factor progression. For example, in breast carcinomas, 8-OHdG has been
(TNF), interleukin-1 (IL-1), IL-6) and chemokines (IL-8, CXC chemo- reported to be increased 8- to 17-fold in breast primary tumors
kine receptor 4 (CXCR4)), as well as alterations in the expression of compared with nonmalignant breast tissue [79–81].
specific microRNAs have also been reported to play a role in oxidative NO•, another free radical implicated in carcinogenesis, is a short-
stress-induced inflammation [69]. This sustained inflammatory/ lived free radical generated from l-arginine [82] that is effective
oxidative environment leads to a vicious circle, which can damage against pathogens. The major part of NO• is synthesized by iNOS,
healthy neighboring epithelial and stromal cells and over a long usually after challenge by immunological or inflammatory stimuli
period of time may lead to carcinogenesis [70]. [82,83]. NO is synthesized from l-arginine by the enzyme nitric oxide
As an example, mutations in the rat sarcoma viral oncogene (Ras) synthase (NOS). The constitutive (calcium-dependent) isoforms,
induce an inflammatory response. Ras, which is mutated in approx- neuronal NOS (nNOS or bNOS) and endothelial NOS (eNOS), produce
imately 25% of all malignancies [71], promotes cell proliferation, small amounts of NO, which acts as a neurotransmitter and
tumor growth, and angiogenesis of malignant cells. During inflam- vasodilator, respectively [84]. The inducible (calcium-independent)
matory stimuli, Ras induces the expression of various inflammatory isoform, iNOS, produces much larger amounts of NO and is expressed
gene products, including the proinflammatory cytokines IL-1, IL-6, only during inflammation. Whereas iNOS can produce injurious
and IL-11 and the chemokine IL-8 [72]. amounts of RNS, eNOS and nNOS produce beneficial amounts under
physiological conditions [85]. iNOS is induced by cytokines such as
interferon-γ, TNF-α, IL-1, and lipopolysaccharide (LPS). LPS activation
induces the translocation of NF-κB, from the cytoplasm to the nucleus,
where it interacts with κB elements in the NOS2 (iNOS) 5′ flanking
region, triggering NOS2 transcription [86].
Defective autophagy of old mitochondria (mitophagy) can also be
a major source of ROS [87]. These ROS produced by damaged
mitochondria can promote tumor development, probably by perturb-
ing the signal transduction adaptor function of p62-controlling
pathways [88].
To control the balance between production and removal of ROS
(Fig. 3), a variety of DNA repair enzymes exist, although antioxidants
are more specific and efficient in protecting cells from radicals. This
antioxidant system includes both endogenous and exogenous and
enzymatic and nonenzymatic antioxidants. GSH is a tripeptide and the
major endogenous antioxidant produced by cells and helps to protect
cells from ROS such as free radicals and peroxides [89]. It is now well
established that ROS and electrophilic chemicals can damage DNA and
Fig. 2. Schematic representation of various transcription factors that are modulated by that GSH can protect against this type of damage [90]. GSH can also
reactive oxygen species. directly detoxify carcinogens through phase II metabolism and
1606 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616

Table 3
A partial list of signaling pathways linked to reactive oxygen species

Signaling intermediate Reference

AHR [98]
AP-1 [99,100]
ATM [101]
cAMP [102]
cAMP-dependent protein kinase A [103]
Cdk5 [104]
Chemokine [70]
c-Myc [99]
CREB [103]
Cyclins and cell cycle regulation [105]
Cytokine network [66]
DNA methylation [106]
DNA repair mechanism [107]
Epidermal growth factor [108]
eNOS [109]
ERK [110]
Fas [111]
FOXO [112]
HIF-1α [113]
Heme oxygenase-1 [114]
IL-10 [115]
iNOS [109]
Integrin [116]
Interferon [117]
JAK/STAT [118]
JNK [119]
MAPK [110]
Fig. 3. Model of a balance between pro-oxidants and antioxidants. Under normal Mismatch repair [120]
conditions, antioxidants outbalance pro-oxidants, but under oxidative conditions, pro- mTor [121]
oxidants prevail over antioxidants, which can lead to many inflammatory diseases, NAD(P)H quinone oxidoreductase 1 [122]
including cancer. NF-κB [123]
Nrf2 [124]
PI3K/Akt [125]
p38 [126]
subsequent export of these chemicals from the cell. On the other hand, p53 [127,128]
elevated GSH levels are observed in various types of cancerous cells Protein kinase C [129]
and solid tumors, and this tends to make these cells and tissues more PPAR-γ [130]
PTEN [131]
resistant to chemotherapy [91–93].
Protein tyrosine phosphatases/Protein tyrosine kinases (PTPs/PTKs) [132]
SODs were the first characterized antioxidant enzymes [94]. Three Sp1 [133]
types of SOD are expressed in human cells, copper–zinc SOD (Cu- TNF [5]
ZnSOD), Mn-SOD, and extracellular-SOD (EC-SOD), all of which are VEGF [134]
able to dismutate two O2•− anions to H2O2 and molecular oxygen. Wnt [135,136]

Catalase is then responsible for detoxification of H2O2 to water. The

GPx's are another group of enzymes capable of reducing hydroper-
oxides, including lipid hydroperoxides, using GSH as substrate. The pathways regulating transcription and cell cycle control, is also
oxidized form of glutathione disulfide is again reduced by the specific activated by H2O2 [137]. In addition, ROS induce both the activation
enzyme glutathione reductase. Peroxiredoxins (Prx's) were first and synthesis of AP-1, a regulator of cell growth, proliferation, and
described 20 years ago, and as for catalase and GPx, the main function apoptosis [138,139], and transcription factors such as STAT3, HIF-1α,
of peroxiredoxins is to reduce alkyl hydroperoxides and H2O2 to the and p53 [118,140,141].
corresponding alcohol or water.
Direct effects of ROS, generally attributed to high concentrations at
the site of damage, include DNA strand breaks, point mutations, Cellular transformation
aberrant DNA cross-linking, and mutations in proto-oncogenes and
tumor-suppressor genes, thus promoting neoplastic transformation Chronic inflammation has been linked to various steps involved in
[7,95]. For example, ROS can reduce the expression and enzymatic carcinogenesis, including cellular transformation, promotion, survival,
activity of the DNA mismatch repair genes mutS homologs 2 and 6 and proliferation, invasion, angiogenesis, and metastasis [65,142]. How
can increase the expression of DNA methyltransferases, leading to a oxidative stress is involved in these various steps is discussed in the
global hypermethylation of the genome [60]. This leads to promoter following sections.
silencing of several genes, such as adenomatous polyposis coli, cyclin- Cancer is a multistage process defined by at least three stages:
dependent kinase inhibitor-2, breast cancer susceptibility gene 1, initiation, promotion, and progression [143–145]. Oxidative stress
retinoblastoma protein, murine double minute 2 (MDM2), and the interacts with all three stages of this process. During the initiation
DNA mismatch repair gene, human mutL homolog 1 [96,97]. stage, ROS may produce DNA damage by introducing gene mutations
On the other hand, low or transient levels of ROS can activate and structural alterations into the DNA. In the promotion stage, ROS
cellular proliferation or survival signaling pathways, such as the NF- can contribute to abnormal gene expression, blockage of cell-to-cell
κB, AP-1, extracellular signal-regulated kinase/mitogen-activated communication, and modification of second-messenger systems, thus
protein kinase (ERK/MAPK), and phosphoinositide 3-kinase/Akt8 resulting in an increase in cell proliferation or a decrease in apoptosis
virus oncogene cellular homolog (PI3K/Akt) pathways (Table 3). of the initiated cell population. Finally, oxidative stress may also
For example, H2O2 is able to degrade IκBα, the inhibitory subunit participate in the progression stage of the cancer process by adding
of NF-κB [137]. Protein kinase C, which participates in a variety of further DNA alterations to the initiated cell population [146].
 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616 1607

In recent years, considerable evidence has demonstrated that ROS the phosphatase counteracting PI3K-dependent Akt activation [167].
are involved in the link between chronic inflammation and cancer Akt may foster tumorigenesis by multiple means [168,169], for example,
[147–149]. Indeed, an important characteristic of tumor promoters is by stabilizing cellular avian myeloblastosis virus oncogene (c-Myc) and
their ability to recruit inflammatory cells and to stimulate them to cyclin D1 or by inducing degradation of the cyclin-dependent kinase
generate ROS [150,151]. Tumor promotion, for example, can be (Cdk) inhibitor, p27 kinase inhibitor protein. Akt is also a profound
inhibited in animal models by the use of agents, including certain inhibitor of apoptosis because of its ability to inactivate proapoptotic
antioxidants as well as steroids and retinoids, that can inhibit the molecules, including caspase-9 and the Bcl-2 homology 3-only protein
phagocyte respiratory burst [148,150]. Moreover, increased levels of Bcl-XL/Bcl-2-associated death promoter, and by triggering the activity
oxidatively modified DNA bases (such as thymidine glycol, 5- of the transcription factor NF-κB. In addition, Akt promotes nuclear
hydroxymethyl-2′-deoxyuridine, and 8-OHdG) have been induced translocation of the ubiquitin ligase MDM2, which counteracts p53-
in the skin of mice by topical phorbol 12-myristate 13-acetate mediated apoptosis. An important aspect of Akt's promotion of cell
exposure [152]. 8-OHdG has also been identified in the epidermis of survival involves alterations in cellular energy metabolism [168,169].
nude mice exposed to near-UV [153]. In addition, genetic damage and Thus, by preventing apoptosis and increasing oxidative metabolism, Akt
neoplastic transformation have been demonstrated in cells cocultured lies at the hub of complex signaling networks that integrate a multitude
in vitro with activated phagocytes [149], and the genotoxic effects of potentially oncogenic signals.
observed include formation of DNA strand breaks [151], sister
chromatid exchange [154], and mutations [155]. Furthermore, the
DNA base modifications observed are characteristic of an attack by Tumor cell proliferation
the reactive oxygen species •OH [156]. Inflammatory cells may also
increase DNA damage by activating procarcinogens to become DNA- Uncontrolled tumor cell proliferation requires the up-regulation of
damaging species; for example, neutrophils can activate aromatic multiple intracellular signaling pathways, including cascades involved
amines, aflatoxins, estrogens, phenols, and polycyclic aromatic in survival, proliferation, and cell cycle progression. The most
hydrocarbons by ROS-dependent mechanisms [148,157]. On the significant effects of oxidants on signaling pathways have been
other hand, both neutrophils and macrophages have themselves observed in the MAPK/AP-1 and NF-κB pathways [170]. The induction
been shown to release large quantities of superoxide, hydrogen of redox-sensitive pathways during tumor cell proliferation is
peroxide, and hydroxyl radical after activation of their redox necessary because cell division presents tremendous energy require-
metabolism [158]. ments and the production of metabolites from energy-generating
In fact, initial experiments on the role of ROS in tumor initiation reactions must be buffered to prevent oxidative damage and
have assumed that oxidative stress acts as a DNA-damaging agent, ultimately cell death [171].
effectively increasing the mutation rate within cells and thus Of the MAPK family, which modulates gene expression through
promoting oncogenic transformation [159]. However, more recent phosphorylation of a wide array of transcription factors, the ERK
studies have revealed that in addition to inducing genomic instability, pathway is the most commonly linked with the regulation of cell
ROS can specifically activate certain signaling pathways and thus proliferation. Activation of the ERK, c-Jun N-terminal kinase (JNK),
contribute to tumor development through the regulation of cellular and p38 subfamilies has been observed in response to changes in the
proliferation, angiogenesis, and metastasis [160]. For example, cellular redox balance [172]. The induction of AP-1 by H2O2, cytokines,
nitrosative stress has been shown to play a critical role in and other stressors, for example, is mediated mainly by JNK and p38
inflammation-associated carcinogenesis by activating AP-1, a repre- MAPK cascades [173]. Once activated, JNK proteins translocate to the
sentative redox-sensitive transcription factor [161], which is involved nucleus and phosphorylate c-Jun and activating transcription factor-2,
in cell transformation and proliferation [139,162]. enhancing transcriptional activities [174,175]. H2O2 can activate
MAPKs and thereby AP-1 in several manners.
Tumor cell survival Redox status has also been shown to have an impact on NF-κB
regulation. NF-κB regulates several genes involved in cell transforma-
One of the key characteristics of tumor cells is their increased tion, proliferation, and angiogenesis [176]. Carcinogens and tumor
ability to survive compared with normal cells. ROS are reported to be promoters, including UV radiation, phorbol esters, asbestos, alcohol,and
tumorigenic by virtue of their ability to increase cell proliferation, benzo(a)pyrene, are among the external stimuli that activate NF-κB
survival, and cellular migration. ROS can induce DNA damage, leading [177,178]. Expression of NF-κB has been shown to promote cell
to genetic lesions that initiate tumorigenicity and subsequent tumor proliferation, whereas inhibition of NF-κB activation blocks cell
progression. On the other hand, ROS can also induce cellular proliferation [179]. Additionally, tumor cells from blood neoplasms,
senescence and cell death and can therefore function as antitumori- and cell lines from various cancers, including colon, breast, pancreas,
genic agents. Whether ROS promote tumor cell survival or act as and squamous cell carcinoma, have all been reported to constitutively
antitumorigenic agents depends on the cell and tissues, the location of express activated NF-κB [180]. The mechanism for activation of NF-κB
ROS production, and the concentration of individual ROS. by ROS is not clear, and the relationship between NF-κB and ROS is
ROS have been reported to play a major role in tumor initiation and complex [123]. Although mild oxidative stress can lead to modest NF-κB
survival induced by a variety of agents in both animal models and activation, extensive oxidative stress can inhibit NF-κB [123]. Further-
humans [158,163,164] by mediating cellular signal transduction path- more, NF-κB can protect cells from oxidative stress through induction of
ways. These signaling pathways are involved in the transmission of the ferritin heavy chain and SOD2 genes, which are both regulated by
inter- or intracellular information and are critical for supporting tumor NF-κB [181,182]. On the other hand, ROS are believed to be implicated as
cell survival and establishing cell fate. The reduced nicotinamide second messengers involved in the activation of NF-κB via TNF and IL-1
adenine dinucleotide phosphate oxidase (Nox) family of enzymes, one [183] and indeed, suppression of TNF and IL-1 was shown to down-
of the potential sources of ROS production, has been reported to regulate the expression of active NF-κB and inhibit proliferation of
promote tumor cell survival and growth [165]. For example, Nox4 and lymphoma and myelogenous leukemia cells [184]. The importance of
Nox5 promote tumor cell survival in pancreatic and lung cancers, ROS in NF-κB activation is further supported by studies demonstrating
respectively [165]. The serine–threonine kinase Akt has been reported that activation of NF-κB by nearly all stimuli can be blocked by
to down-regulate antioxidant defenses and promote tumor cell survival antioxidants, such as l-cysteine, N-acetylcysteine, thiols, green tea
[166]. ROS have also been reported to activate Akt by inhibiting polyphenols, and vitamin E [185,186], although this might be not very
phosphatase and tensin homolog deleted from chromosome 10 (PTEN), specific because antioxidants have multiple targets [187]. Likewise, NF-
1608 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616

κB activity was increased in cells that overexpressed SOD and decreased of endogenous CXCR4 gene expression by CXCR4 short hairpin RNA
in cells overexpressing catalase [188]. inhibited the proliferation, adhesion, chemotaxis, and invasion of
Kinases, such as protein kinase C, can also be activated by H2O2 mucoepidermoid carcinoma cells [210]. In addition, recent data point
and redox cycling quinones [189,190]. Similarly, H2O2 leads to the to a role for the small guanosine triphosphatase Rac1 in motility and
activation of protein kinase B/Akt, which is associated with heat shock invasion of tumor cells in vitro by altering cell–cell and cell–matrix
protein 27 [191]. adhesion. For example, Rac1 activity induces ROS production in
That ROS such as H2O2 and superoxide anion induce mitogenesis endothelial cells. These ROS can mediate Rac1-induced loss of cell–cell
and cell proliferation has now been demonstrated in several adhesion in primary human endothelial cells and thus might loosen
mammalian cell types [192]; and a reduction in cellular oxidants via the integrity of the endothelium [211].
supplementation with antioxidants such as superoxide dismutase, It is becoming clear that a number of steps in the metastatic
catalase, β-carotene, and flavonoids inhibits cell proliferation in vitro cascade, such as invasion, intravasation, and extravasation, are
[193]. However, paradoxically high concentrations of ROS can trigger regulated by redox signaling [212]. One such redox signaling molecule
apoptotic or necrotic cell death [194–196]. is the electrophilic cyclopentenone prostaglandin 15d-PGJ2 (15-
deoxy-12,14-prostaglandin J2), an inflammatory molecule [213],
Tumor cell invasion which can affect redox signaling through the posttranslational
modification of critical cysteine residues in proteins such as actin,
Oxygen radicals may augment tumor invasion and metastasis by vimentin, and tubulin [214,215]. The fact that 15d-PGJ2 can alter the
increasing the rates of cell migration. During transformation into cytoskeleton [212] coincides with decreased migration and increased
invasive carcinoma, epithelial cells undergo profound alterations in focal-adhesion disassembly, which might have important implica-
morphology and adhesive mode, resulting in a loss of normal tions in the inhibition of metastatic processes such as invasion,
epithelial polarization and differentiation and a switch to a more intravasation, and extravasation. These results suggest a role for redox
motile, invasive phenotype. For example, treatment of mammalian signaling pathways, rather than direct cytoskeletal disruption, in the
carcinoma cells with hydrogen peroxide before intravenous injection mechanism of 15d-PGJ2 in cancer cells.
into mice enhances lung metastasis formation, indicating that an Finally, Cheng et al. demonstrated that ROS enhance the
important function for ROS is the seeding of metastatic tumor cells transendothelial migration of melanoma cells during intravasation
[197]. This might be due to a decreased attachment of tumor cells to and that this mechanism could potentially be triggered by ultraviolet
the basal lamina or alternatively be due to the increased activity or radiation through the increased expression of thioredoxin-interacting
expression of proteins that regulate cellular motility. For instance, protein and inhibition of thioredoxin [216].
oxidative stress regulates the expression of intercellular adhesion
protein-1 (ICAM-1), a cell surface protein in endothelial and epithelial Tumor cell angiogenesis
cells, most likely because of the activation of NF-κB. ICAM-1 together
with IL-8 regulates the transendothelial migration of neutrophils and Solid tumors induce an angiogenic response by the host blood
has a potential function in tumor metastasis [198]. vessels to form a new vascular network for the supply of nutrients and
On the other hand, it is believed that the matrix metalloprotei- oxygen [217]. This neovascular response is partly responsible for
nases (MMPs) play the central role, and their increased expression tumor growth and metastatic spread [218,219]. Angiogenesis in
reportedly is associated with the invasion and metastasis of malignant tumors is controlled by the so-called “angiogenic switch,” which
tumors of various histogenetic origins [199]. For example, Mori et al. allows the transition from low invasive and poorly vascularized
found that MMP-13, MMP-3, and MMP-10 were remarkably up- tumors to highly invasive and angiogenic tumors. To increase further
regulated by the oxidant directly, and their activities were critically in size, tumor cells express a set of molecules that initiate tumor
implicated in the invasive potential induced in NMuMG cells in the vascularization.
reconstituted model [200]. Another subgroup of MMPs, gelatinases A number of cellular stress factors, including hypoxia, nutrient
(MMP-2 and -9), which are key enzymes for degrading type IV deprivation, and ROS, are important stimuli of angiogenic signaling
collagen and are thought to play a critical role in tumor invasion and [220]. In addition, overexpression of Ras has been linked to
metastasis [199], were also found to be activated posttranscriptionally vascularization of tumors [221]. Indeed, transformation by Ras
by prolonged oxidative treatment. These effector molecules activated stabilizes HIF-1α and up-regulates the transcription of vascular
under prolonged oxidative stress relate chronic inflammation to endothelial growth factor-A (VEGF-A). Moreover, chemical antiox-
malignant transformation, in particular to the invasive potential of idants inhibit the mitogenic activity of Ras, indicating that ROS
cells, at least at a molecular level. participate directly in malignant transformation. Finally, ROS stabilize
MMPs are capable of cleaving most components of the basement HIF-1α protein and induce production of angiogenic factors by tumor
membrane and extracellular matrix [201]. The activation of MMPs, such cells [222].
as MMP-2, probably occurs by the reaction of ROS with thiol groups in The HIF system plays a significant role in angiogenesis, and the
the protease catalytic domain [202]. In addition to their role as key molecular mechanisms of its regulation have recently been charac-
regulators of MMP activation, ROS have been implicated in MMP gene terized. In addition, HIF-independent mechanisms that involve a
expression [203]. Both hydrogen peroxide and nitric oxide donors, as number of other molecules and transcription factors such as NF-κB
well as the increased expression of iNOS, stimulate the expression of and p53 have been described. p53 may interact with the HIF system
several MMPs (MMP-1, MMP-3, MMP-9, MMP-10, MMP-13) [203]. In but may also have direct effects on angiogenesis regulators or
fibroblastic cells, the sustained production of H2O2 recently was shown interfere with translation mechanisms of angiogenesis factors.
to activate MMP-2 and to increase cell invasion [204]. Oxidative stress One other major factor in angiogenesis is VEGF, which is produced
may also modulate MMP expression by activation of Ras, or direct by the cells to stimulate the growth of new blood vessels. VEGF
activation of the MAPK family members ERK1/2, p38, and JNK, or induces angiogenesis by stimulating endothelial cell proliferation and
inactivation of phosphatases that regulate these proteins [160]. migration primarily through the receptor tyrosine kinase VEGF
In addition, several studies have reported the involvement of receptor 2, fetal liver kinase 1/kinase insert domain receptor (Flk1/
chemokines and chemokine receptors in the invasion and metastasis KDR). VEGF binding initiates tyrosine phosphorylation of KDR, which
of various types of tumors [205–208]. The metastatic potential of results in activation of downstream signaling enzymes including
chemokines is attributed to their ability to induce the expression of ERK1/2, Akt, and endothelial nitric oxide synthase (eNOS), which
MMPs, which facilitate tumor invasion [208,209]. Moreover, silencing contribute to angiogenic-related responses in endothelial cells [134].
 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616 1609

A number of oncogenes and tumor-suppressor genes that are doxorubicin [245]. Likewise, expression of MDR-associated protein 1
normally associated with cell transformation (Ras, c-Myc, murine is elevated in inflamed intestine of patients with Crohn disease or
sarcoma 3611 oncogene, human epidermal growth factor receptor-2, ulcerative colitis [246]. Thus, enhanced states of inflammation
c-Jun, and steroid receptor coactivator) regulate angiogenesis through influence proteins that are strongly linked with drug resistance.
up-regulation of VEGF or down-regulation of thrombospondin-1 In addition to the effects caused by inflammation, several
(TSP-1), an angiogenesis suppressor [223,224]. Furthermore, mutated chemotherapeutic agents have also been shown to activate the
p53 up-regulates VEGF and, in contrast, wild-type p53 decreases VEGF transcription factor NF-κB in human lung and cervical cancers and in T
production and increases TSP-1 [225]. Angiogenic factors such as cells [247–249]. These agents are paclitaxel, vinblastine, vincristine,
VEGF, fibroblast growth factor (FGF), and platelet-derived growth doxorubicin, daunomycin, 5-fluorouracil, cisplatin, and tamoxifen.
factor are released into the tumor microenvironment by tumor or Activation of NF-κB by these agents has been linked in turn with
inflammatory cells in response to various stimuli, such as ROS [226]. chemoresistance through serine phosphorylation of IκBα [250,251].
The released growth factors activate endothelial cells that give rise to Various in vitro studies have supported a link between NF-κB
new blood vessels [227,228]. activation, cytokine production, and chemoresistance. One pathway
Monte et al. have demonstrated that lymphocyte-induced angio- through which NF-κB can be activated is the Toll-like receptor (TLR)
genesis is triggered by ROS stimulation and that this response can be pathway. TLRs generally signal via the adapter protein myeloid
blocked by the administration of a free radical scavenger to tumor- differentiation primary response gene 88 leading to activation of NF-
bearing mice [229,230]. In addition, the administration of H2O2 or an κB and production of proinflammatory cytokines. Activation of TLR
oxidative stress-producing drug (doxorubicin) to normal mice signaling in ovarian cancer cell lines by exogenously added LPS
activated in vivo angiogenesis [229]. resulted in an activated NF-κB pathway, which promoted secretion of
Because of reduced physiological tissue oxygen tension (hypoxia), proinflammatory cytokines and subsequently conferred resistance to
which occurs during tumor initiation, tumors often become hypoxic. paclitaxel [252,253]. Also, TNF receptor signaling promotes NF-κB
Under hypoxic conditions, cells activate signaling pathways, which activation and has been linked to chemoresistance. For example,
regulate proliferation, angiogenesis, and death. Cancer cells have exposure of breast cancer cells to exogenously added TNF-α results in
adapted to these pathways, effectively allowing tumors to survive and selection for breast cancer cells that overexpress NF-κB, leading to
even grow under adverse hypoxic conditions [160]. This adaptation of increased cancer cell survival and resistance to ionizing radiation
tumor cells to hypoxia contributes to the malignant phenotype and to [254]. At the same time, cytokines produced by stromal cells in the
aggressive tumor progression [231], and low oxygen tension in tumor microenvironment (e.g., IL-1 or TNF-α) could potentially
tumors is associated with increased metastasis and poor survival of activate the NF-κB pathway in cancer cells and thus contribute to
patients with several forms of squamous tumor [232,233]. HIF-1α chemoresistance. These data call for functional in vivo studies to
responds to these changes by specifically decreasing the oxygen (or elucidate the involvement of the inflammatory tumor microenviron-
hypoxia) level and up-regulating several genes to promote survival ment in NF-κB-dependent chemoresistance.
under low-oxygen conditions and thus promoting angiogenesis. Another mechanism that might be involved in chemoresistance is
In conclusion, although previous sections indicate that all different increased levels of GSH in cancer cells [92]. In particular, the
substages of tumor development are affected by ROS and inflamma- overexpression of glutathione S-transferases (GSTs), the enzymes
tion, early stages of cancer development (e.g., cellular transforma- that catalyze the conjugation of reduced glutathione to electrophilic
tion), involving DNA damage, are, however, most affected by ROS- compounds [255], as well as efflux pumps may reduce the reactivity of
generated inflammation. For example, colitis may develop into colon various anticancer drugs [256]. The increase in the GST levels occurs
cancer after inflammatory infiltration, increased production of ROS, by transcriptional activation mediated by Nrf2 [257]. Indeed, using
impairment of antioxidant defenses, DNA damage, and genetic and genetic manipulation, Lau et al. have demonstrated a strong positive
epigenetic alterations, resulting in the transformation of epithelial correlation between Nrf2 levels and resistance of three cancer cell
cells [234]. Or, bronchitis, which can lead to lung cancer, clearly links lines to chemotherapeutic drugs such as cisplatin, doxorubicin, and
pro-oxidants, generated by cigarette smoke, to inflammation of the etoposide [258]. Chemical activation of Nrf2 by pretreatment with
bronchus and eventually transformation of lung cells into lung cancer tert-butylhydroquinone also increased survival of neuroblastoma
[235]. Similarly pancreatitis and esophagitis, both induced by tobacco cells in response to the three drugs tested [259]. Consistent with
and alcohol, may transform normal tissue into pancreatic or these findings, the role of Nrf2 in determining the efficacy of cisplatin
esophageal cancer if the antioxidant system is not sufficiently was also demonstrated in ovarian cancer cells using small interfering
effective [236,237]. RNA knockdown of Nrf2 [260]. Moreover, many Kelch-like ECH-
associated protein 1 (Keap1) mutations or loss of heterozygosity in
Chemoresistance the Keap1 locus has been identified in lung cancer cell lines or cancer
tissues [261,262]. Keap1 mutations or loss of heterozygosity resulted
Despite many decades of research, the mechanisms underlying in inactivation of Keap1 or a reduced expression of Keap1, which up-
chemoresistance are still poorly understood. There is growing regulated the protein level of Nrf2 and transactivation of its
evidence that the inflammatory tumor microenvironment modulates downstream genes [261,262]. Similar to Nrf2, the protective effect
not only cancer development but also cancer responsiveness and of heme oxygenase-1 (HMOX-1, or HO-1) in normal cells may protect
resistance to conventional anticancer therapies [238]. Experimental from oxidative stress-related diseases. However, such an effect is
studies have led to the identification of various cancer cell-intrinsic undesirable in cancer because it provides a selective advantage for
resistance mechanisms, e.g., activation and/or overexpression of drug cancer cells to survive. Consistent with this notion, HMOX-1 has been
transporter proteins (e.g., P-glycoprotein), altered expression of found to be overexpressed in various tumor types. It is believed that
detoxifying enzymes (e.g., glutathione S-transferase), or resistance overexpression of HMOX-1 facilitates cancer cell growth and survival
to apoptosis/senescence pathways [239–242]. in many ways, such as stimulating rapid growth of cancer cells,
For example, an inflammatory response induces changes in the enhancing cancer cell resistance to stress and apoptosis, promoting
expression and activity of multidrug-resistance (MDR)-associated angiogenesis of tumors, and aiding in metastasis of tumors [263]. In
protein transporters, greatly affecting drug responses [243,244]. It has addition to HMOX-1, other Nrf2-downstream genes such as Prx1, GPx,
been shown that acute inflammation suppresses the drug transporter and thioredoxin reductase were also up-regulated in many cancer
P-glycoprotein (PGP) in the liver, whereas it activates PGP in kidneys, cells or tissues and may contribute to chemoresistance [264–266]. In
resulting in changes in the pharmacokinetics of the PGP substrate ovarian cancer, constitutive activation of ERK activity has been
1610 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616

associated with high tumorigenicity and chemoresistance [267,268]. On the other hand, hypoxia is a principal signature of the tumor
In addition, functional analyses employing knockdown of MKP3, a microenvironment and is considered the most important cause of
member of the subfamily of protein tyrosine phosphatases known as clinical radioresistance and local treatment failure. The response of
dual-specificity phosphatases (MKPs) [269,270], and ectopic over- cells to ionizing radiation is strongly dependent upon oxygen, which
expression revealed the role of MKP3 in negatively regulating ERK1/2 is traditionally explained by the “oxygen fixation hypothesis” [280].
activity and inhibiting tumorigenicity and chemoresistance in vitro Oxygen is so far the best radiosensitizer. De Ridder et al. demonstrated
and in vivo. MKP3 is capable of dephosphorylating ERK1/2 by protein– that iNOS, activated by proinflammatory cytokines, can radiosensitize
protein interactions via a mitogen-activated protein kinase interaction tumor cells through endogenous production of NO [280]. They further
motif within the N-terminal ERK1/2-binding domain [271]. observed that this radiosensitizing effect is transcriptionally con-
trolled by hypoxia and by NF-κB. Consistently, NF-κB inhibition has
Radioresistance been used as an approach to radiosensitize tumor cells, aiming at
stimulating apoptosis and inhibiting DNA repair. Moreover, the
Acquired tumor radioresistance can be induced during radiother- inflammatory mediators TNF-α and NO have been repeatedly used
apy owing to tumor repopulation [272]. Although tumor radio- as targets to radiosensitize tumor cells [281–285].
resistance stands as a fundamental barrier limiting the effectiveness of
radiation therapy, the exact molecular mechanisms underlying the Stem cell survival
radioadaptive response are largely unknown (Fig. 4). Olivieri et al.
[273] first described an adaptive response of human lymphocytes to Cancer stem cells (CSCs) are cancer cells that have the ability to
ionizing radiation. Since then, a substantial number of reports have generate tumors through the processes of self-renewal and differen-
made a strong case for the existence of cellular radioprotective tiation into multiple cells. Such cells persist in tumors as a distinct
mechanisms that can be activated in response to a small dose of population and cause relapse and metastasis by giving rise to new
ionizing radiation. It is assumed that a specific prosurvival signaling tumors. The existence of CSCs may have several implications in cancer
network is induced in irradiated mammalian cells. treatment, including disease identification, selection of drug targets,
The elevated basal NF-κB activity in certain cancers has been prevention of metastasis, and development of new intervention
linked with tumor resistance to chemotherapy and radiation [274]. strategies.
NF-κB in adaptive radioresistance is evidenced in mouse epidermal The first conclusive evidence for CSCs was published in 1997 [286],
cells [275] and human keratinocytes, and inhibition of NF-κB blocks and to date CSCs have been isolated from both leukemias and a variety
the adaptive radioresistance [275]. Human breast cancer cells treated of solid tumors, including breast, brain, pancreatic, prostrate, ovary,
with fractional γ-irradiation show an enhanced clonogenic survival and colon cancers [287–293]. The pathways that regulate self-renewal
and NF-κB activation [276,277]. Blocking NF-κB inhibited the adaptive of CSCs include wint (Wnt), Notch, Hedgehog, and tumor-suppressor
radioresistance. These results provide the first evidence that activa- genes such as PTEN and tumor protein 53 [294]. Although redox
tion of NF-κB is required for signaling the radioadaptive resistance by balance plays an important role in the maintenance of stem cell self-
exposure to radiation. Together with the assumption that NF-κB is renewal and in differentiation, redox status in CSCs has yet to be
able to regulate more than 150 effector genes, these results suggest explored. However, given the similarity between normal stem cells
that NF-κB plays a key role in tumor radioadaptive resistance under and CSCs and the fact that redox status plays an important role in
fractional ionizing radiation. Furthermore, in a study [278] that cancer cell development, it is tempting to speculate that redox status
immunocytochemically examined the levels of activated NF-κB may have a role in CSC survival. A recent study by Diehn et al.
protein in pretreatment cancer specimens and in resected specimens demonstrated that, similar to normal stem cells, subsets of CSCs in
of patients with chemoradiotherapy resistance, the cancers expressed human and murine breast tumors have lower ROS levels than do the
higher levels of cytoplasmic NF-κB than did the adjacent nonmalig- corresponding nontumorigenic cells [295]. The group further showed
nant mucosa. Furthermore, Sandur et al. suggest that transient that lower levels of ROS were associated with increased free radical
inducible NF-κB activation provides a prosurvival response to scavenging systems and that pharmacologic depletion of these
radiation that may account for the development of radioresistance scavengers significantly decreased clonogenicity and resulted in
[279]. radiosensitization of CSCs. Additionally, two studies showed that

Fig. 4. Model of the sensitivity of normal cells versus cancer cells to reactive oxygen species. Normal cells are hypersensitive to ROS if not adequately protected by antioxidant
mechanisms, which may lead to cancer formation. Cancer cells, on the other hand, have up-regulated antioxidant mechanisms (glutathione, SOD, catalase, and others) that will
protect them against ROS, as can be observed in, for example, the case of radioresistance.
 S. Reuter et al. / Free Radical Biology & Medicine 49 (2010) 1603–1616 1611

CD133+ CSCs conferred chemoresistance to cisplatin and doxorubicin therapy. Numerous agents that can interfere with redox cell signaling
(known ROS generators) in ovarian cancer cells [296] and hepatocel- pathways have been identified [9,312,313]. These include nutraceu-
lular carcinoma [297], respectively. These studies further indicate that ticals derived from fruits, vegetables, spices, grains, and cereals. They
redox status may be important in maintaining CSC survival. have been shown to suppress tumorigenesis in preclinical models.
Whether these agents can inhibit tumor growth in patients remains to
Stromal cell signaling be elucidated.

Cancer progression must involve both genetic and behavioral

Acknowledgments
changes in cancer cells, and these changes are in part driven by the
cancer-associated stromal cells and tumor microenvironment
We thank Michael Worley for carefully editing the manuscript. Dr.
[298,299]. The stromal component of the normal prostate epithelium,
Aggarwal is the Ransom Horne, Jr., Professor of Cancer Research. This
for example, consists of smooth muscle, fibroblasts, vascular endo-
work was supported by a grant from the Clayton Foundation for
thelial cells, nerve cells, inflammatory cells, insoluble matrix, and
Research (B.B.A.), a core grant from the National Institutes of Health
soluble factors [300]. Studies by De Marzo et al. highlight the role of
(CA-16672), a program project grant from the National Institutes of
inflammation in prostate cancer, suggesting that atrophic lesions are
Health (NIH CA-124787-01A2), and a grant from the Center for
an early event in prostate carcinogenesis [301]. The macrophages in
Targeted Therapy of the M.D. Anderson Cancer Center. Simone Reuter
the tumor microenvironment produce ROS and RNS. The resulting
was supported by a grant from the Fonds National de la Recherche
increases in superoxide, hydrogen peroxide, hydroxyl radical, and free
Luxembourg (PDR-08-017).
iron damage DNA, causing genetic mutations and initiating cancer
progression. Tissue and cell recombination studies demonstrate the
important regulatory role of fibromuscular stroma and stromal References
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