Accumulating evidence shows that chronic inflammation can promote all stages of tumorigenesis, including DNA damage, limitless replication, apoptosis evasion, sustained angiogenesis, self-sufficiency in growth signaling, insensitivity to anti-growth signaling, and tissue invasion/metastasis. Chronic inflammation is triggered by environmental (extrinsic) factors (eg, infection, tobacco, asbestos) and host mutations (intrinsic) factors (eg, Ras, Myc, p53). Extensive investigations over the past decade have uncovered many of the important mechanistic pathways underlying cancer-related inflammation. However, the precise molecular mechanisms involved and the interconnecting crosstalk between pathways remain incompletely understood. We review the evidence implicating a strong association between chronic inflammation and cancer, with an emphasis on colorectal and lung cancer. We summarize the current knowledge of the important molecular and cellular pathways linking chronic inflammation to tumorigenesis. Specifically, we focus on the role of the mitochondria in coordinating life- and death-signaling pathways crucial in cancer- related inflammation. Activation of Ras, Myc, and p53 cause mitochondrial dysfunction, resulting in mitochondrial reactive oxygen species (ROS) production and downstream signaling (eg, NFκB, STAT3, etc.) that promote inflammation- associated cancer. A recent murine transgenic study established that mitochondrial metabolism and ROS production are necessary for K-Ras–induced tumorigenicity. Collectively, inflammation-associated cancers resulting from signaling pathways coordinated at the mitochondrial level are being identified that may prove useful for developing innovative strategies for both cancer prevention and cancer treatment.
Inflammation, ROS, and the Mitochondria
α, IL-1β, NFκB, STAT3, and COX-2) decreases the incidence and spread of certain tumors (eg, colorectal cancer). In general, inflammatory /immune components necessary at one stage of tumorigenesis may be completely dispensable during another stage.[3,6] Also, adaptive transfer of inflammatory cells or overexpression of certain cytokines promotes tumor formation.
The major sources of ROS in the setting of inflammation-associated cancer include (1) NADPH oxidase present in phagocytes and other cells and (2) mitochondria. In non-phagocytic cells, over 95% of ROS formed during normal metabolism originate from the electron transport chain (ETC) in the inner mitochondrial membrane in close proximity to mtDNA. ROS-induced mtDNA damage is implicated in a wide range of pathologic processes, including carcinogenesis, aging, and degenerative diseases.[85,86] Emerging studies suggest that mitochondrial ROS form crucial intermediates between environmental and host stimuli that result in inflammation-associated cancer (see Figure). Mitochondrial metabolism via the pentose phosphate shunt and mitochondrial ROS production from the Qo site of complex III in the ETC are necessary for K-Ras–induced tumorigenesis. Hypoxia, as occurs in solid tumors, stimulates the expression of HIFs, which are important transcription factors involved in coordinating the cellular response to hypoxia. They regulate mitochondrial metabolism and ROS production, yet at the same time, mitochondrial ROS regulate HIF expression.[reviewed in 51,87] Accumulating evidence establishes that asbestos fibers induce lung epithelial cell apoptosis via the mitochondria-regulated death pathway and that mitochondrial ROS have a causal role. A recent study showed that a Helicobacter pylori toxin, vacuolating cytotoxin A, induces mitochondria-regulated apoptosis by juxtapositioning the mitochondria with endosomes. This finding implicating the mitochondria provides a potential mechanistic link between chronic Helicobacter infections and gastric cancer. Thus, the available information supports the hypothesis that the levels of mitochondrial ROS are important in regulating the balance between normal physiologic signaling (low mitochondrial ROS levels) compared with the signaling in inflammation-associated cancer that promotes tumorigenesis (high mitochondrial ROS levels). In this regard, mitochondria-targeted antioxidants present attractive agents for cancer prevention or treatment. However, the mechanisms of action of these antioxidants may not be as expected. For example, in recent studies, we found that mitoquinone inhibits tumor cell growth, but that, instead of acting as an antioxidant, it appears to act by inducing ROS formation in cancer cells, causing the induction primarily of autophagy instead of apoptosis. Further studies are required to deepen our understanding of the potential therapeutic benefits of mitochondria-targeted redox agents for inflammation-associated cancer.
Given the close proximity of mtDNA to the mitochondrial ETC and the lack of protective histones, mtDNA damage resulting from oxidative stress may be important in the pathogenesis of inflammation-associated cancer. For example, with asbestos, lung mesothelial cell mtDNA damage is evident following exposure to a four-fold lower concentration of crocidolite asbestos than the crocidolite doses required to cause nuclear DNA damage. Also, several lines of evidence implicate mtDNA oxidative injury as a key trigger of apoptosis that may be important in inflammation-associated cancer, including: (1) that cell death is more closely associated with mtDNA oxidative lesions than with nuclear DNA lesions, (2) that mtDNA damage precedes ATP depletion and mitochondrial dysfunction, (3) that enhancing mtDNA repair blocks cell death, and (4) that deficiency of mtDNA repair enhances cell death.[reviewed in 51,86] Base excision repair (BER) is the principal pathway for repairing oxidative mtDNA damage. Epidemiological data suggest that the levels of 8OHdG, the most common DNA base change arising from oxidative stress, is linked with various cancers and neurodegenerative diseases.[85,86,91-94] 8OHdG induces mutations in replicating cells by preferentially mispairing with adenine during DNA synthesis, thereby increasing the incidence of G:C to T:A transversions. DNA glycosylases have a key role in BER pathways: they recognize the oxidized DNA adduct and excise the damaged base. 8-oxo-guanine DNA glycosylase (Ogg1), which is responsible for repairing 8OHdG, has a dual function: it preferentially recognizes 8OHdG opposite cytosine and then excises it via its apurinic/apyrimidic lyase activity. All mtDNA BER repair proteins, including Ogg1, are nuclear-encoded and imported into mitochondria. Overexpression of mitochondria-targeted Ogg1 blocks intrinsic apoptosis in ROS-exposed vascular endothelial and asbestos-exposed HeLa cells.[90,95,96] We recently extended these findings to AEC exposed to oxidative stress (asbestos or H2O2). Further, using Ogg1 mutants incapable of 8OHdG DNA repair, we showed that Ogg1 functions in a role independent of DNA repair by preserving mitochondrial aconitase levels. Mitochondrial aconitase has a dual role: (1) it serves as an iron-sulfur– containing tricarboxycylic acid cycle enzyme that is a mitochondrial redox-sensor susceptible to oxidative degradation and (2) it maintains mtDNA by mechanisms that are independent of its catalytic activity.[98-100] Mitochondrial aconitase co-precipitates with frataxin, an iron chaperone protein that is as good as Ogg1 at preventing aconitase oxidative inactivation.[97,101] Given the importance of p53 in inflammation-associated cancer, it is of interest that Ogg1 is under transcriptional regulation by p53.[102,103] Collectively, these findings suggest critical crosstalk between the mitochondria (ROS, aconitase, Ogg1, etc) and p53 that is likely important in inflammation-associated cancer.
Activation of oncogenic transcription factors can be triggered through pattern recognition receptors, by exposure to components of bacteria, viruses, and interestingly, mtDNA.[104,105] Chronic inflammation /infection can lead to extensive cellular damage in target organs (eg, necrotic epithelial cells and macrophages in tumors), and this results in the release of damage-associated molecular pattern (DAMP) or pathogen-associated molecular pattern (PAMP) molecules.[reviewed in 6,56] DAMPs include IL-1α, high mobility group B1 molecule (HMGB1), and other molecules that work in concert to facilitate inflammation. The underlying mechanisms are the subject of ongoing studies. Circulating mtDNA and mitochondrial DAMPs can be detected in patients with trauma, a finding that may account for the increased risk of multi-organ dysfunction in these patients. These investigations illustrate the diverse mechanisms by which alterations in the mitochondria can impact inflammation-associated cancer. It is unclear whether epithelial cells or immune/inflammatory cells are the primary source of DAMPs in tumors. It will be of interest to determine whether chronic inflammation/tissue injury results in the release of mtDNA, and if so, whether this is crucial for driving inflammation-associated cancer. Further studies are necessary to better understand the precise molecular details by which mitochondrial respiration, mitochondrial ROS production, and mtDNA damage affect specific components of inflammation-associated cancer.
Inflammation and Tumor-Promoting Signaling Pathways
Tumor cells, carcinogen-exposed epithelial cells, and inflammatory cells utilize NFκB, a tightly regulated transcription factor, to activate a number of genes coding for proteins involved in inflammation-associated cancer, including cytokines, growth factors, adhesion molecules, angiogenic factors, proto-oncogenes (eg, Myc), COX-2, and nitric oxide synthase.[reviewed in: 3,6,7,106] NFκB, a dimer of two Rel-family proteins (p50 and p65), is activated in the cytoplasm by diverse cellular conditions including excess ROS, hypoxia, and HIF-1α. It is also regulated autonomously by genetic alterations that lead to phosphorylation of its inhibitor protein (IκBα). The phosphorylation of IκBα results in the proteolytic degradation and subsequent translocation of IκB to the nucleus, where it binds to and regulates the DNA. NFκB is also activated downstream of signaling by inflammatory cytokines (eg, TNF-α, IL-1β) as well as by the toll-like receptor–MyD88 pathway that is stimulated by microbes and tissue damage. NFκB can have divergent effects in various models of carcinogenesis that likely relate to the balance between activating downstream pro- and anti-tumorigenic effects.[106-109)] Murine transgenic studies have established a key role for NFκB signaling pathways in colitis-associated cancer, liver cancer, and breast cancer metastasis.[reviewed in 4,7,14] NFκB activation by TNF-α augments nuclear entry of Wnt/β-catenin in inflammation-associated gastric cancer, as well as in colonic crypt cells—a finding that is likely crucial for promoting tissue invasion/metastasis. Asbestos causes prolonged, dose-dependent transcriptional activation of NFκB-dependent genes in vitro and in vivo by a ROS-dependent mechanism.[reviewed in 112] In murine models that inhibit IKKβ-dependent NFκB activation, acute inflammation is exacerbated while chronic intestinal inflammation is attenuated. These findings underscore how critical the context of inflammation (eg, acute vs chronic) is in regulating the pro-inflammatory and anti-apoptotic effects of NFκB. The collective evidence suggests that NFκB has primarily pro-tumorigenic effects but that an anti-inflammatory role can occur. Further studies are necessary to determine the precise role of pharmacologic and genetic targeting of the NFκB-dependent pathways in various cancer preventative and treatment strategies.
STAT3, like NFκB, is a transcription factor that is often constitutively activated in tumors and immune cells. It mediates a number of crucial tumorigenic signaling pathways (eg, cell proliferation, apoptosis, Myc expression, evasion of immune surveillance).[reviewed in 4] The STAT family contains seven members, but STAT3 has been most closely implicated in inflammation-associated cancer.[reviewed in 21] STAT3 signaling is essential for stem-cell renewal as well as for persistent NFκB activation in tumor cells.[114,115] Further, mitochondrial STAT3 is essential for Ras-dependent oncogenic transformation. The molecular mechanism(s) that account for the presence of STAT3 in the mitochondria are unclear, but apparently do not depend on increased STAT3 transcriptional activity, nor on changes in mtDNA-encoded proteins. Rather, the presence of mitochondrial STAT3 appears to be mediated by greater mitochondrial ETC activity. A firm role for STAT3 in colitis-associated cancer is suggested by the finding of a reduced incidence of colon cancers in STAT3-deficient mice.[reviewed in 14] Also, a colitis-inducing strain of Bacteroides fragilis that is implicated in colorectal cancer is a potent activator of STAT3 in humans and mice. Mutations in EGFR result in downstream IL-6 production and STAT3 phosphorylation in lung adenocarcinomas.[118,119] Although the precise molecular details await further study, the available experimental evidence supports an important role for the interconnected signaling cascade of NFκB–IL-6–STAT3 in the development of inflammation-associated cancer.
Cancer-related inflammation remains a significant challenge to healthcare providers, as well as to investigators studying the basic mechanisms underlying tumorigenesis. Largely because the pathogenesis of inflammation-associated cancer is incompletely understood, there are currently limited therapeutic techniques for modifying cancers that occur in the setting of chronic inflammation. The accumulating evidence links a wide variety of chronic inflammatory conditions to diverse groups of cancers (see Table 1), providing firm support for the role of inflammation-associated cancer as an important event in the pathogenesis of cancer. It may even be the seventh hallmark of cancer, as suggested by Mantovani et al. In this review, we summarized the evidence implicating a growing number of key molecular and cellular pathways mediating cancers that occur in the setting of chronic inflammation (see Figure). In particular, we reviewed current knowledge implicating the mitochondria, especially mitochondrial ROS, as a central regulator in inflammation-associated cancer. As summarized in Table 2, there is much that we know about what promotes inflammation-associated cancer, but there remain a number of crucial missing pieces of experimental evidence that will be necessary to definitively prove a causal relationship between inflammation and cancer. In this regard, future in vivo studies utilizing novel targeted murine transgenic approaches, such as those described herein, will be necessary to advance our understanding of the field. Strategies aimed at enhancing mitochondrial DNA integrity and/or increasing mitochondrial antioxidant defenses may prove beneficial in reducing malignant transformation after exposure to noxious agents (eg, tobacco, PM) and host mutations that result in inflammation-associated cancer. Importantly, the significance of these investigations is that they provide the molecular rationale for developing urgently needed and novel strategies for cancer prevention and treatment.
Financial Disclosure: The authors have no significant interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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