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.
Mechanisms Underlying Inflammation-Associated Cancer
The last decade has witnessed much insight into inflammation-associated cancer; however, major gaps in our understanding remain. Table 2 highlights some of what we know regarding inflammation-associated cancer, as well as some of the critical questions that require further investigation to definitively prove a causal role for inflammation-associated cancer in tumorigenesis. In this section, we summarize the emerging evidence highlighted in Table 2. We focus on recent studies indicating an important role for the mitochondria, especially mitochondrial ROS production, as an upstream regulator of cancer-related signaling pathways that promote inflammation and tumorigenesis.[reviewed in 51,52]
Inflammatory Cells in Tumorigenesis
Although a wide variety of cancers are associated with chronic inflammation and/or infection (see Table 1), it is unclear whether chronic inflammation is sufficient to induce cancer in the absence of a carcinogen. Further, acute inflammation is not associated with cancer, and not all chronic inflammatory conditions augment cancer risks (eg, psoriasis, rheumatoid arthritis, asthma), for reasons that are uncertain. A causal role for inflammation in cancer is suggested by the finding that IL-10 deficiency promotes somatic mutations in a murine IBD model in the absence of exogenous carcinogens. There are some data suggesting that ROS derived from either inflammatory/immune cells[54,55] or the mitochondria of epithelial cells act as the central endogenous carcinogens that drive cancer-promoting signaling pathways important in inflammation-associated cancer, as depicted in the Figure. It is unclear whether ROS/RNS produced by neutrophils and macrophages are sufficient to induce the kinds of epithelial cell DNA damage that result in tumorigenesis. Inflammatory cells also release cytokines, such as TNF-α, that can promote chronic oxidative stress in affected tissue. Further investigations are required to formally verify a causal relationship between chronic inflammation/infection and cancer, as well as to determine whether ROS are the only endogenous carcinogens.
As reviewed in detail elsewhere[7,14,56], one of the most compelling arguments linking inflammation-associated cancer to tumorigenesis is the observation that drugs that inhibit the production of prostaglandins during inflammation reduce the risk of various cancers, such as colorectal, esophageal, gastric, lung, breast, and ovarian cancer. These drugs include nonspecific NSAIDs, such as aspirin, and selective COX-2 inhibitors. COX-2 is an inducible form of cyclo-oxygenase that is activated in chronic inflammation. It is highly expressed in nearly all tumors. COX-2 expression is necessary and sufficient to induce tumorigenesis in multiple in vitro and animal models.[reviewed in 2,7] It mediates the production of certain inflammatory cytokines that can act as tumor promoters, such as IL-6. Randomized clinical trials show that NSAIDs decrease colon adenoma formation, an important precursor of colorectal cancer.[7,56] In breast cancer cells, COX-2 overexpression induces oxidative stress as well as chromosomal abnormalities (eg, fusions, breaks, and tetraploidy) that contribute to tumorigenesis. Despite these remarkable advances in our understanding, no anti-inflammatory strategy is currently approved to prevent or treat cancer, although several are under development (eg, anti–IL-6 therapy for multiple myeloma). As reviewed in detail elsewhere[3,59], additional studies are required to determine which patient populations are appropriate for cancer preventative agents that target COX-2 or other relevant signaling pathways.
The tumor microenvironment contains a wide variety of inflammatory and immune cells, cytokines, and chemokines that have pro- and anti-tumorigenic activity, the balance of which likely dictates clinical outcome.[2-8] Experimental in vivo evidence unequivocally establishing the role of particular immune/inflammatory cells and cytokines/chemokines in tumorigenesis is lacking. The most common immune cells in tumors are tumor-associated macrophages (TAMs) and T cells. TAMs, which are the major source of cytokine production in the tumor microenvironment, promote tumorigenesis in several ways. They produce protein factors that stimulate tumor cell growth, directly and indirectly (eg, by stimulating angiogenesis), and they stimulate metastasis by producing matrix-degrading enzymes.[5,6] TAMs are classified either as M1 or M2 macrophages, depending on their response to various stimuli. M1 TAMs respond to interferon (IFN)-γ or microbial exposure by expressing high levels of cytokines involved in anti-tumor and anti-microbial activity (eg, TNF-α, IL-1, IL-6, IL-12, IL-23), while M2 TAMs are proangiogenic/tissue-remodeling macrophages that display reduced expression of IL-12 and increased expression of the anti-inflammatory cytokine IL-10 following exposure to IL-4, IL-10, or IL-13.[3,6] The M1 and M2 TAM phenotypes are plastic, based on their gene expression profiles. The protumorigenic effects of TAMs are suggested by the finding that TNF-α–deficient mice are protected against drug-induced skin cancer.[60,61] Also, TAMs augment Wnt signaling via a TNF-α–dependent pathway in gastric cancer; this pathway is necessary for growth and for epithelial-mesenchymal cell transition that is important in metastasis. Phase 1 and II clinical trials are underway examining the role of TNF-α antagonists in patients with renal cancer as well as advanced cancers. As reviewed in detail elsewhere, studies in transgenic mice have established a protumorigenic role for IL-1. The finding of increased skin and colitis-related cancers occurring in mice deficient in the atypical chemokine receptor D6 establishes a prominent role for CC chemokines in tumorigenesis. In this context, it is not surprising that a high tumor TAM content generally foreshadows a poor prognosis.
T cells can also impact cancer outcomes. Increased levels of CD8+ cytotoxic T lymphocytes and CD4+ helper 1 (Th1) cells portend a better prognosis in certain tumors (eg, colon, melanoma, pancreatic, multiple myeloma, lung) and comprise a therapeutic approach to the treatment of these cancers. In contrast, a T-cell deficiency can augment tumor formation. Additional investigation is necessary to determine why certain T-cell subsets are pro-tumorigenic in one cancer but anti-tumorigenic in another. Also, it is unknown whether there is a common upstream inflammatory signal (eg, mitochondrial ROS production) that is activated in all malignancies, and if so, whether this regulates the balance between TAM and T-cell pro- and/or anti-tumorigenic activities.
Inflammation and Oncogenes/Tumor Suppressor Genes
Similar to Ras, the Myc oncogenes are mutated in many human cancers and alter mitochondrial function (eg, increased electron transport, oxygen uptake, and ROS production) in a way that induces the rapid cell growth that is a crucial element of tumorigenesis. Growth factors and chemokines produced in the setting of inflammation-associated cancer augment Myc overexpression in cancer cells, thereby driving Ras activation and abnormal DNA synthesis. In a murine Myc model of pancreatic cancer, the initial wave of angiogenesis is mediated by the inflammatory cytokine IL-1β. Interestingly, a recent gene expression profile study showed that the Myc network of transcription programs accounts for most of the similarity between embryonic stem cells and cancer cells. Myc activation can trigger mitochondria-regulated apoptosis, whereas Myc-induced DNA damage and cellular transformation are prevented by mitochondria-targeted antioxidants.[71,72] Thus, the emerging evidence suggests that the mitochondria are important downstream effector organelles in both Myc- and Ras-induced oncogenic transformation (see Figure).
The tumor suppressor protein p53 is an important transcriptional factor for multiple proteins involved in the cellular DNA damage response, and it is likely important in inflammation-associated cancer.[see for review 73] Following DNA damage caused by oxidative stress (eg, that resulting from exposure to tobacco, asbestos, etc), an intact p53 response prevents mutations from accumulating by increasing the expression of genes that inhibit cell growth, thereby increasing the time available for DNA repair. However, if DNA damage is extensive, p53 activation can augment apoptosis by inducing pro-apoptotic genes while inhibiting expression of anti-apoptotic genes, ultimately causing mitochondrial dysfunction and intrinsic apoptosis. Because of its central role in directing cellular life and death outcomes, it is not surprising that mutations in p53 gene family members are common in human tumors. Mitochondrial ROS block wild-type p53 function and promote the formation of p53 mutations.[reviewed in 4,51] Mutations in p53, some from inflammation-associated oxidative stress, are evident in the epithelium of cancer cells and in inflamed, but non-dysplastic epithelial cells. This suggests that genomic changes can result from chronic inflammation. Altered p53 expression has also been implicated in the pathophysiology of pulmonary fibrosis, including that due to asbestos, as well as in pulmonary fibrosis–associated bronchogenic lung cancer.[75-80] For example, increased p53 protein expression is detected in the bronchiolar and alveolar epithelium of humans with idiopathic pulmonary fibrosis and in rodents exposed to asbestos.[75-80]Furthermore, increased p53 levels are detected in lung cancers of patients with asbestosis, and p53 point mutations are widely evident in the respiratory epithelium of smokers and asbestos-exposed individuals. p53 mediates asbestos-induced, mitochondria-regulated apoptosis in lung epithelial cells, and this is blocked in cells incapable of producing mitochondrial ROS. Notably, loss of p53 results in mtDNA depletion, altered mitochondrial function, and increased H2O2 production. Considerable evidence, reviewed in detail elsewhere, has established that p53 is a crucial regulator of mitochondrial function, including ROS generation and mtDNA repair following oxidative damage, as well as mitochondrial biogenesis and mtDNA replication. Although formal evidence is lacking, it is likely that loss of wild-type p53 function augments the deleterious effects induced by Ras and Myc on mitochondrial function described above. Thus, p53 has a key role in regulating the response to cellular DNA damage caused by exposure to oxidative stress, and likely plays a role in the pathogenesis of inflammation-associated cancer. Future investigations are required to better understand how the Ras, Myc, and p53 pathways are interconnected.
As reviewed in detail elsewhere,[4,8] chronic inflammation can effect each of the six hallmarks of tumorigenesis identified by Hanahan and Weinberg, including limitless replicative potential, sustained angiogenesis, evasion of apoptosis, self-sufficiency in growth signaling, insensitivity to anti-growth signals, and tissue invasion/metastasis. The evasion of immune surveillance mechanisms and genetic instability due to inflammation-associated cancer have each been proposed as the seventh hallmark of cancer—again emphasizing the role of inflammation in cancer.[4,84] Inflammation-associated cancer induces oxidative stress that can lead to DNA damage and cellular stress, which in turn cause abnormalities in mitosis (eg, through chromosomal abnormalities) and metabolism (eg, through the Warburg effect, or increased glucose uptake for glycolysis). Although beyond the scope of this review, nearly 30 different cancer therapies targeting these assorted mechanistic hallmarks of inflammation-associated cancer are in various stages of development.[reviewed in 8] A crucial unresolved issue is whether inflammatory signaling in susceptible tissues (eg, the lungs of smokers) can be altered so as to favor adaptive immunity (anti-tumorigenic activity) rather than pro-tumorigenic activity.
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