Virchow is credited with suggesting the causal link between inflammation and cancer in the 19th century. He based his conclusion on the astute observation that tumors often developed in the setting of chronic inflammation and that inflammatory cells were present in tumor biopsy specimens. Accumulating evidence that has emerged in the last decade or so has shed light on the underlying mechanisms accounting for the strong association between chronic inflammation and each step of tumorigenesis.[reviewed in 2-8] Notably, nearly 90% of all cancers are due to environmental factors and somatic mutations, whereas causal germ-line mutations are infrequent. Nearly 20% of cancer deaths worldwide are attributed to chronic infection and/or inflammation, with gastrointestinal and lung cancers accounting for a substantial portion of the total burden.[1,9] An estimated 30% of cancers may be linked to exposure to tobacco and/or other airborne pollutants, and 20% can be attributed to chronic infections. In general, a normal adaptive immune response is anti-tumorigenic; however, dysregulated innate and/or adaptive immune responses can be pro-tumorigenic. Human neutrophils can induce malignant transformation, which suggests that phagocytic cells are carcinogenic. Mantovani et al[3,4] proposed that genetic instability resulting from cancer-related inflammation represents the seventh hallmark of tumorigenesis, in addition to the six proposed by Hanahan and Weinberg (limitless replication, sustained angiogenesis, evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, and tissue invasion/metastasis).
In this review, we summarize the current knowledge supporting the association between chronic inflammation and cancer, highlighting the information that has been published since our 2002 ONCOLOGY review. We then review the emerging evidence regarding important molecular and cellular pathways that link chronic inflammation to cancer. Emphasis will be placed on the pivotal role of the mitochondria in coordinating life- and death-signaling pathways important in inflammation-associated cancer. Collectively, the studies we review are revealing the crucial mechanisms that underlie inflammation-associated cancer and that may prove useful for developing novel cancer preventative and therapeutic strategies.
Cancers Associated With Chronic Inflammation
Epidemiological evidence firmly supports a link between chronic inflammation and cancer that occurs in various organs (Table 1). The inflammatory conditions implicated are quite diverse; they include a wide array of chronic infections, exposure to noxious agents that trigger inflammation (eg, gastric acid reflux, tobacco, asbestos), and auto-immune conditions. Inflammation-associated cancer consists of white blood cells, notably tumor-associated macrophages (TAM) and T lymphocytes; increased generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS); altered cytokine/chemokine expression; and augmented molecular signaling via nuclear factor kappa B (NFκB), signal transducer and activator of transcription proteins (STATs), cyclooxygenase-2 (COX-2), and others.[reviewed in 2-8] In this section we focus on two widely studied cancers linked to chronic inflammation: colorectal cancer and lung cancer.
The best-established link between chronic inflammation and cancer is seen in colorectal cancer that develops in patients with inflammatory bowel disease (IBD; eg, ulcerative colitis and Crohn disease). These patients have a five- to seven-fold increased risk of developing colorectal cancer.[12-15] Nearly 43% of patients with ulcerative colitis develop colorectal cancer after 25 to 35 years. Therapeutic strategies for the treatment or prevention of IBD aim to reduce the endogenous levels of tumor necrosis factor (TNF)-α, which is a key pathophysiologic element of the disease. NFκB regulates multiple pathways involved in inflammation-associated cancer (eg, cytokine expression, angiogenesis, apoptosis, and COX-2 expression). TNF-α regulates NFκB, in part by receptor-mediated activation of inhibitory κB kinases (IKK) that stimulate degradation of proteins responsible for retaining the transcription factor in the cytosol, thereby enabling the translocation of NFκB to the nucleus. In a murine model of IBD, the development of colitis-associated colorectal cancer can be inhibited either by blocking TNF-α expression or by generating mice with colon epithelial cells that are deficient in IKK-β.[16,17] These findings in mice concur with the clinical observation that inhibition of the NFκB-regulated protein COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for colorectal cancer in humans with IBD by nearly 80%.[18,19] The synthesis of prostaglandin E2 (PGE2) by COX-2 induces the production of inflammatory cytokines such as interleukin (IL)-6. Exposure to inflammatory cytokines (eg, IL-6, IL-10) causes the activation of the signal-transducing STAT proteins that work in conjunction with NFκB to regulate many genes involved in tumorigenesis.[reviewed in 4,21-23] The importance of STAT3 in colorectal cancer is evident in the finding that the development of tumors in a murine model of IBD is reduced in STAT3-deficient mice and through pharmacologic inhibition of IL-6. The STAT pathway also regulates erythropoiesis and angiogenesis, both of which augment the availability of oxygenated blood to otherwise hypoxic tumors.[4,21-23] This pathway would provide an indirect mechanism for STAT-mediated tumor promotion. Collectively, these investigations provide the molecular basis for future studies on the role of inflammatory signaling through TNF-α, NFκB, STAT3, IL-6, and other signaling proteins in the etiology of inflammation-associated cancer. Hopefully, the information gained will prove useful in the management of colorectal cancer as well as IBD.
Lung cancer causes nearly 1 million deaths worldwide every year and is the leading cause of cancer deaths. Although tobacco exposure is evident in nearly 90% of all patients with lung cancer, other chronic airway inflammatory conditions (eg, asbestosis, silicosis, exposure to airborne particulate matter (PM), idiopathic pulmonary fibrosis, tuberculosis, etc) are all independent risk factors for lung cancer and may account for a proportion of the non-smoking related cases. Tobacco smoke contains nearly 5000 reactive chemicals, including over 1015 free radicals in the gas phase and 1018 free radicals per gram in the tar phase. These include H2O2, •OH, and organic radicals. As reviewed in detail elsewhere,[26-28] chronic inflammation has a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Smokers with COPD have a 1.3- to 6-fold increased risk of lung cancer compared with smokers without COPD, and this is likely due to persistent lung inflammation.[2,27,29] A meta-analysis demonstrated a strong indirect relationship between forced expiratory volume in 1 second (FEV1) and lung cancer risk. Low-grade emphysema, without airway obstruction, is an independent risk factor for the development of lung cancer. Although beyond the scope of this review, some of the potentially important molecular mechanisms underlying cancer associated with tobacco-induced inflammation include the production of ROS, inflammatory signaling (eg, via TNF-α, NFκB, IL-6, and others), single nucleotide polymorphisms in inflammatory cytokines (IL-1α and IL-1β), and increased ceramide and epithelial growth factor receptor (EGFR) signaling.[26-28] Interestingly, COPD-like inflammation induced by nontypeable Haemophilus influenza, which is the most common bacteria colonizing the airways of patients with COPD, promotes K-Ras–induced lung cancer in mice. Notably, a recent study showed that mitochondrial metabolism is crucial for allowing mitochondrial ROS production at the Qo site of complex III, and that mitochondrial metabolism and ROS production were both required for mediating K-Ras–induced lung cancer in mice. Macrophage migration inhibitory factor, an inflammatory cytokine, is produced at sites of bleomycin-induced lung injury in mice and functions to prevent apoptosis and promote tumor growth. These innovative studies reveal insights into the pathogenesis of lung cancer occurring in the setting of emphysema-associated inflammation and should provide a rationale for future novel treatment strategies. Additional studies are necessary to understand why inflammation persists after smoking cessation as well as how inflammation in patients with COPD modulates disease expression.[29,35]
Lung cancer can also result from chronic pulmonary inflammation and fibrosis following exposure to other environmental toxins (eg, asbestos, silica, PM, beryllium). Further, a large cohort analysis of data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial showed that pulmonary scarring was associated with an elevated lung cancer risk (hazard ratio 1.5; 95% confidence interval 1.2-1.8). In this section we highlight the role of asbestos. Asbestos is a term for a group of naturally occurring hydrated silicate fibers whose resilient strength and chemical properties make them ideal for a variety of building and insulation purposes. Asbestos causes an estimated 100,000 to 140,000 lung cancer deaths per year worldwide and contributes to nearly 5% to 7% of all lung cancers.[37,38] There are two classes of asbestos fibers: (1) serpentine fibers—curly-stranded structures, among which chrysotile is the principal commercial variety, and (2) amphibole fibers—straight, rod-like fibers (eg, crocidolite, amosite, tremolite, and others). Compared to chrysotile, amphibole fibers are more fibrogenic and carcinogenic, in part because their biopersistence in the lung results in chronic inflammation. Asbestos is an established carcinogenic agent that can induce chronic inflammation of the lung and pleura, ROS production, DNA damage, and cell death in all the major lung target cells (eg, bronchial and alveolar epithelial cells [AEC], mesothelial cells).[see for review: 39,40] Substantial investigations have shown that the extent of AEC injury and lack of sufficient AEC repair are important determinants of pulmonary inflammation and fibrosis following exposure to a wide variety of noxious agents, including asbestos. There is a direct correlation between the levels of asbestosis seen in asbestos workers and the risk of developing lung cancer. Asbestos-induced ROS cause DNA damage, such as single- or double-strand breaks, intra- and inter-strand cross-linking, and base damage.[see 42,43 for reviews] Repair of these lesions in most instances will restore the physiologic DNA structure, but abnormal DNA repair may result in gene mutations, chromosomal aberrations, and ultimately cell transformation. Early studies in our group showed that the repair of complex, inflammation-associated DNA damage, such as that caused by the exposure of cells to activated neutrophils, is slow compared to the repair of single-strand breaks, suggesting that residual DNA damage may lead to mutations or other cellular abnormalities that can promote tumorigenesis. ROS-induced DNA damage is implicated in mediating the synergistic effect between asbestos and cigarette smoke for lung cancer risk.[see for review: 45,46] Convincing evidence, reviewed elsewhere, has established that asbestos induces AEC apoptosis via the mitochondria-regulated (intrinsic) death pathway and involves mitochondrial ROS production. Interestingly, studies in transgenic mice suggest that Rac1-mediated mitochondrial H2O2 production from asbestos-exposed alveolar macrophages is necessary for the induction of pulmonary fibrosis. However, further studies are required to better understand the molecular mechanisms underlying the link between asbestos-induced inflammation/pulmonary fibrosis and lung cancer.
One possibility is that diverse environmental stimuli, including asbestos and other lung carcinogens (eg, silica), but not inert particulates, cause pulmonary inflammation and fibrosis via activation of Nalp3 inflammasomes, which can stimulate caspase-1.[48,49] Nalp3 is a member of the NLR family of over 20 proteins. These proteins contain multiple functional domains, including an N-terminal protein-protein interaction domain that is necessary for caspase activation, a caspase recruitment domain (CARD), a central nucleotide-binding domain, and a C-terminal leucine-rich repeat domain. Nalp3 inflammasome formation occurs when activated Nalp3 recruits caspase-1 and ASC, an adaptor molecule, via CARD-CARD interactions. Asbestos- and silica-induced lung inflammatory cell recruitment, cytokine production (eg, of IL-1β and others), and silicosis are all reduced in mice deficient in Nalp3, ASC, or caspase-1.[48,49] Moreover, by using specific pharmacologic inhibitors and targeted murine knockouts, it was found that the factors that appear essential for Nalp3 inflammasome activation include fiber uptake into phagocytic cells, an intact actin cytoskeleton, and ROS generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase during phagocytosis. Thus, asbestos- and silica-induced Nalp3 inflammasome activation may be a novel therapeutic target for treatment/prevention of the underlying causes of inflammation-associated cancer.
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