From Inflammation to Cancer

The following sections are included:

• Foreword

• About the Editors

• List of Main Contributors

Gastrointestinal (GI) cancers are among the top cancer types in terms of incidence and mortality worldwide. The underlying infection and inflammation play a major role in the development of GI cancers. In this chapter, the etiology and epidemiology association between major GI cancers and associated inflammation diseases will be discussed, including the association between inflammatory bowel diseases and colorectal cancer (CRC); Barrett's esophagus and esophageal cancer; hepatitis virus infection or steatohepatitis and hepatocellular carcinoma (HCC); Helicobacter pylori (H. pylori) infection and gastric cancer (GC).

Inflammation is a host defense against invading pathogens, damaged tissue and cellular irritates such as toxins in local tissue. The well-known clinical signs of inflammation include redness, swelling, warmth and pain at the site of infection or trauma. The increase in vascular diameter leads to increased local blood flow, hence manifested as redness and warmth; followed by the adhesion of leukocytes to the local blood vessel walls. Consequently the increase of vascular permeability in local blood vessels gives rise to swelling or edema and pain. In general, the initiated inflammatory responses result in the recruitment of various types of immune cells to eliminate foreign pathogens, clear damaged cells and trigger tissue-repairing processes. Both macrophages and neutrophils in the innate immune system constitute a first line of host defense against invading pathogens. When these cells become activated after phagocytosing pathogens, they can further activate other immune cells including dendritic cells and T cells. Moreover, many types of immune cells can recognize pathogenic invaders via a diversity of receptors for pathogen-associated molecular patterns (PAMPs) expressed on the surface of various microbes, which plays an important role for the induced adaptive immunity during an inflammatory response at local sites. In addition to infection-triggered inflammatory response, there is increasing evidence indicating that inflammation is also present and contributes to cancer cell proliferation, angiogenesis and metastasis. Thus, further understanding of the mechanistic modulation of inflammatory response may lead to the development of novel strategies for cancer treatment. Here, we review the general process and immune mechanisms of inflammation.

While the connection between inflammation and tumorigenesis was suggested a long time ago, key factors linking these two processes remain to be completely understood. A defining characteristic of the malignant tumor cell is its inappropriate growth and strong invasive and metastatic capability. Studies have shown that during chronic inflammation, several factors were released from the inflammatory cells, and genetic and epigenetic abnormalities were accumulated in the progenitor cells, which may be sufficient to confer malignant growth properties. This chapter mainly focuses on and discusses the fundamental mechanisms linking chronic inflammation and tumorigenesis.

The link between inflammation and cancer has been recognized for a long time. Instead of a simple summation of molecular events in single cells, carcinogenesis results from the complex interaction of cancer-stem cells and tumor-permissive microenvironment. The tumor-permissive microenvironment is featured by the suppression of cell-mediated immune response, pro-angiogenesis and inhibition of apoptosis. A number of soluble bioactive factors including various cytokines and growth factors, produced by tumor cells or non-tumor cells, contribute to the formation of such an inflammatory microenvironment by the persistent activation of multiple intracellular signaling pathways such as NF-κB and STAT3 pathways.

Carcinogenesis is a multi-stage process resulting from the accumulation of many genetic and epigenetic changes. However, it is more than a simple summation of molecular events in single cells. The role of inflammatory microenvironment in carcinogenesis was well recognized, eventually revolutionizing our strategies to cancer treatment and prevention.

Helicobacter pylori infection treatment is a dynamic process dependent on antibiotic resistance. Triple therapy remains the first line approach to patients. Sequential therapy may hold the key to recalcitrant patients however, further data is required. Novel alternative therapies are in the early days and still require further investigation. Treatment of gastric cancer patients is currently sub-optimal and advances in molecular and targeted agents shows promise, although trial data is still in progress. On a population level the treatment of H. pylori is not a feasible option for the prevention of gastric cancer. Future studies should take a multidisciplinary approach to treating gastric cancer patients to provide the most favorable outcomes for patients.

Colorectal cancer is one of the most devastating complications of chronic colitis in the setting of inflammatory bowel disease (IBD).¹ Current strategies in the reduction or management of colitis-associated colorectal cancer are chemoprophylaxis, colonoscopy surveillance of at-risk individuals and proctocolectomy is a potentially curative treatment for those with precancerous dysplasia or early cancer. Maintaining colitis in remission may reduce colorectal carcinogenesis in IBD. 5-aminosalicylic acid compounds may have additional chemoprophylactic effects and ursodeoxycholic acid reduces colorectal carcinogenesis in the setting of primary sclerosing cholangitis. Antitumour necrosis factor agents and thiopurine analogues may not only treat colitis but also have chemoprophylactic benefits. New endoscopic imaging techniques, such as chromoendoscopy, may improve the yield of identifying flat dysplasia during surveillance colonoscopy. This chapter summarises the epidemiology of dysplasia in IBD, its classification, and outlines the current endoscopic surveillance strategies, treatment algorithm and dysplasia chemoprophylaxis.

Chronic hepatitis B virus (HBV) infection is a major cause of liverassociated morbidity and mortality worldwide. An increased knowledge of hepatitis B virology, immunology and natural history has identified active HBV replication as the key driver of immune-mediated liver injury and disease progression. In the past two decades, the clinical use of interferon and oral antiviral agents has improved long-term prognosis of chronic hepatitis B patients. To achieve a better treatment response, important issues regarding the treatment candidacy, end points of therapy and predictors of sustained virological response remain to be investigated. Currently, emergence of drug resistance is the major drawback of oral antiviral therapy. In the future, the use of new antiviral agents with greater potency and a high genetic barrier to resistance, as well as on-treatment monitoring of virological response, may result in improved outcomes in HBV therapy. Hepatocellular carcinoma (HCC) is a common liver cancer worldwide and is highly prevalent in Asia. Surgical treatment of HCC includes partial hepatectomy and liver transplantation. Liver transplantation is indicated in patients fulfilling the Milan criteria. The Milan criteria have been challenged with less restrictive criteria, the UCSF criteria which did not significantly increase the post-transplant tumor recurrence rate. For patients who had unresectable lesions, loco-regional therapy included transarterial chemoembolization, percutaneous acetic or ethanol acid injection, or radiofrequency ablation is recommended depending on the size and number of tumor nodules. Sorafenib, an oral form multi-targeted kinase inhibitor, can prolong the overall survival of patients with advanced HCC.

Infection with hepatitis C virus (HCV) is the second commonest cause of hepatocellular carcinoma (HCC) worldwide, the number one cause in Japan and a major reason for increasing HCC incidence in North America and Australia. HCV is an RNA virus whose genome does not enter the host nucleus to damage DNA directly. In chronic HCV infection, viral persistence is related to suppression of host innate immunity and dampening of the adaptive immune response. Conversely, immunosuppression facilitates viral replication and progression of chronic hepatitis C (CHC). In cell culture and transgenic mice, HCV proteins, such as core, NS3 and NS5A produce multiple effects on transcriptional regulation of gene expression and cell signaling of potential relevance to inflammatory recruitment, cell death and proliferation of hepatocytes. This has led many authors to conclude that HCV has direct hepatocarcinogenic properties, but there are potential flaws in this interpretation related to the experimental systems used. Instead, clinicopathological correlations indicate that the HCV pathway to liver cancer proceeds via chronic liver inflammation (CHC) and cirrhosis, and this takes decades to unfold. Other host determinants of HCC risk in HCV-infected patients include older age, male gender, genetic factors/ethnicity, previous heavy alcohol intake, hepatitis B virus (HBV) infection, obesity, type 2 diabetes and cigarette smoking. While interactions between viral proteins, alcohol and hepatic lipid metabolism or insulin receptor signaling are evident experimentally, these co-morbid environmental factors are likely to operate principally by worsening the inflammatory activity and rate of fibrotic progression of CHC to cirrhosis. Conversely, effective antiviral therapy abolishes liver inflammation and injury when sustained virus response (SVR) is obtained, and this reduces incidence of HCC by over 80%, even when cirrhosis is established. Continuous interferon therapy does not diminish HCC risk when SVR is not obtained. After resection of HCC, antiviral treatment reduces late recurrence related to development of new cancers rather than residual disease, and this improves patient survival. The approach to treatment of HCV genotype 1 is changing. "Triple therapy" with pegylated interferon, ribavirin and a direct antiviral, such as telaprevir or boceprevir, improves efficacy during first treatment and retreatment of non-SVR cases. Since hepatocarcinogenesis with HCV is intimately related to continuing hepatic necroinflammatory activity and cirrhosis, it is likely this will further reduce HCC rates by eradicating liver inflammation and preventing cirrhosis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Surgical treatment, including hepatic resection and liver transplantation, is the most effective therapy and is considered potentially curative. However, less than 20% of HCC can be treated surgically because of multicentric tumors, early vascular invasion, extra hepatic metastasis, shortage of donor organs, poor hepatic reserve or other co-morbidities precluding major surgery. In such instances, a variety of interventional treatments can be offered in order to improve the prognosis of the patient.

Chronic infection and inflammation contribute to about 25% of all cancer cases worldwide. Specifically, hepatocellular carcinoma (HCC), the frequent malignant cancer with the third leading cause of cancer death, is a representative malignancy showing a strong association with chronic inflammatory disease. HCC develops almost exclusively in cirrhotic livers resulting from viral hepatitis, alcoholic or fatty liver disease. Several clinical studies indicate that >85% of HCCs retain markers for HBV and/or HCV. Cytokines, the most common mediators linking inflammation and cancer, show altered expression in cirrhotic disease and HCC, which can be categorized as pro- or anti-carcinogenesis. Thus, understanding the signaling pathway and the exploration of cytokine-based clinical management is representing a promising therapeutic strategy. In this chapter, we provide a general overview of the connection of inflammation and HCC and highlight the process of translating basic science to clinical managements by introducing two cytokines — tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Though promising, current cytokine-based therapies are at an early stage, for example, TNF-α have both pro- and anti-tumor effects, which lead to contradictory strategies in clinic applications. As our understanding of the mechanistic connections between inflammation and cancer development accumulate, the cytokine-based clinical management should be more specific and efficient in HCC prognosis, diagnosis and treatment.

The link between inflammation and cancer development has been reported in numerous research publications and substantiates the involvement of nuclear factor-κB (NF-κB), a versatile transcription factor, in inflammatory bowel disease (IBD). NF-κB can be activated by a wide array of inducers including bacteria, fungi and viruses, cytokines and stress. NF-κB is identified as a key regulator in the immunopathogenesis of IBD and genetic polymorphisms in NF-κB have supported the connection between IBD and colorectal cancer progression. Importantly, the role of cytokines and chemokines secreted by the epithelial cells and infiltrating cells such as macrophages and neutrophils contributes to the sustained and constitutive activation of NF-κB in these cells. In addition, NF-κB hyperactivation has been observed in colorectal cancer and alters the expression of target genes such as TNF-α, IL-6, IL-23, COX-2, NOD2/CARD15 and matrix metalloproteases. In this chapter, we discuss our current understanding of the role of NF-κB in Crohn's disease, ulcerative colitis, Barrett's metaplasia and colorectal cancer. Inhibiting NF-κB activity has been shown to suppress inflammation and slow down cancer progression. A number of genes and proteins are discussed in detail and their specific roles in various stages of the disease pathogenesis reveal the complexity of this intracellular signaling pathway. In this context, complete elucidation of the role of NF-κB signalling in gastrointestinal tract-associated inflammation and cancer may lead to identification of novel therapeutic strategies for IBD.

Tumor necrosis factor (TNF)-α was originally identified as a factor, which can induce hemorrhagic necrosis in tumor tissues in mouse. Subsequent studies have further revealed that its expression is under the control of an inflammation-induced transcription factor, NF-κB and that it can, in turn, activate NF-κB. Moreover, accumulating evidence indicates the crucial involvement of NF-κB in various types of carcinogenesis in mice, particularly one which develops after administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion. However, it remains elusive on which factor(s) is responsible for NF-κB activation in this process. Treating wild-type (WT) mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced leukocyte infiltration, and attenuated subsequent tumor formation. Furthermore, administration of Etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by leukocytes. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis. Because evidence is accumulating to indicate that TNF-α can promote tumor development and progression, and metastasis formation in various mouse models, targeting TNF-α may be useful in treating various types of cancers, particularly chronic colitis-associated colon cancer.

PPARγ is a nuclear receptor transcription factor involved in both carcinogenesis and inflammation. It displays a high expression in adipose tissue controlling adipogenesis and fat metabolism but is also expressed in equivalent levels in colorectal tissue where it plays a role in metabolism but also in signal transduction, proliferation and motility. PPARγ roles in inflammatory bowel disease and in colorectal cancer have been studied and some of their aspects have been elucidated. An inflammation- suppressing effect of PPARγ seems to emerge in most experimental models. Additionally, PPARγ has anti-tumor effects in most models of inflammation-induced but also sporadic carcinogenesis. The current knowledge on PPARγ in these processes and perspectives on therapeutic opportunities will be the subject of this paper.

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that are activated by a unique proteolytic mechanism. PARs are widely expressed in the gastrointestinal tract, which is replete with proteinases that participate in digestion and host defense, as well as those produced by the bacterial flora of the gut. Mounting evidence indicates that PARs take active part in the pathophysiology of inflammatory diseases and cancer. As a signal transducer of extracellular proteinase activity, PARs regulate inflammation and promote tumorigenesis through a variety of mechanisms. It is emerging that PARs may be novel therapeutic targets for a variety of settings including inflammation and cancer. In this chapter, we discuss the general characteristics of the PAR family and the important roles of PARs in the processes of inflammation and tumor development.

Tumor markers are currently playing an important role in colorectal cancer (CRC) detection and management. Fecal occult blood testing with either a guaiac or preferably an immunochemical test may be used to screen for early CRC. Following curative surgery for CRC, regular measurements of serum CEA is recommended, especially for patients that may be candidates for liver resection or systemic therapy, should recurrences develop. For patients with advanced CRC under consideration for treatment with the anti-EGFR antibodies, panitumumab or cetuximab, the mutational status of k-ras should be determined. K-ras positive patients should not receive these treatments. Finally, regular measurement of CEA is recommended in patients with advanced CRC undergoing treatment for CRC.

Identification of genetic biomarkers is a highly active area of research. With the development of microarray technology, researchers could characterize tumors at the genomic level, and this catalyzed a shift toward the discovery of genetic biomarkers for cancer. Genetic biomarkers could be used to identify the presence of a tumor at an early stage and to predict the natural course of an individual tumor, both of which are key factors in improving survival rate of patients. For hepatocellular carcinoma (HCC), the 5-year survival rate is only about 5%, the identification of novel biomarkers would clearly be beneficial. Physicians could use biomarkers to determine the best treatment option for patients with a particular tumor characteristic. This is especially important given the heterogeneity of HCC. To date, serum α-fetoprotein (AFP) level measurement is a standard means for detecting HCC, but its sensitivity and specificity are limited. Novel biomarkers are therefore being developed in order to improve the diagnosis and prognosis of HCC. In this chapter, the potential genetic biomarkers that could be used for detection, subtype classification, and estimation of prognosis are discussed.

Inflammation is a self-defense biological process against various challenges, such as biological invasion, chemical and physical injuries. However when it becomes unsolved it could progress to chronic inflammation and further develop into cancer. Indeed, the relationship between inflammation and cancer has been well established. It involves different inflammatory cells including macrophage recruitment and neutrophil infiltration at injurious sites. All these could reciprocally stimulate various cytokines and chemokines secretion and also expression of some important transcriptional factors, namely NF-κB, STAT3 and HIF1γ into the microenvironment of tumors. These would activate different oncogenic processes including increase in proliferation and survival of cancer cells, promotion of angiogenesis at cancer sites, and enhancement of metastasis and invasion of cancer cells in distant organs. It is envisaged that concurrent inhibition of these pathological pathways or blocking several inflammatory mediators in the whole inflammatory cascade represents the current therapy and future targets for inflammation-associated cancerous diseases.

The following sections are included:

• Index