Chapter 1
General Introduction
Chung Wah Wu and Jun Yu* Institute of Digestive Disease and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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); Barretts esophagus and esophageal cancer; hepatitis virus infection or steatohepatitis and hepatocellular carcinoma (HCC); Helicobacter pylori (H. pylori) infection and gastric cancer (GC).
Introduction Cancer is one of the worlds leading causes of death. Every year, 14% of the worlds population die of cancer. The relationship between inflammation and cancer has long been recognized. This is based on the findings that tumors often arise at sites of chronic inflammation. Infiltration of inflammatory cells and upregulation of chemokines and cytokines are frequently present in tumors, implicating a strong association between the inflammation mechanism and tumorigenesis. Epidemiological studies have shown that chronic inflammation
* Corresponding author. E-mail: junyu@cuhk.edu.hk
C. W. Wu and J. Yu
increases the risk of numerous cancers, including the most common ones such as lung cancer, gastric cancer and liver cancer. The processes of inflammation and tumorigenesis share many common molecular pathways such as the nuclear factor-B (NF-B) pathway, RASRAF signaling pathway, prostaglandin-synthesis pathway, etc. This has made possible the use of some anti-inflammatory drugs as potential anticancer agents. For example, cyclooxygenase 2 (COX2) inhibitor, a class of nonsteroidal anti-inflammatory drug, is able to reduce the risk and mortality rate of certain cancers.
How inflammation and cancer are linked The connection between inflammation and cancer can be best described by two pathways: the extrinsic pathway and the intrinsic pathway. An extrinsic pathway is driven by inflammatory conditions which present before a malignant change and can subsequently increase cancer risk at the inflammatory site. Examples of the extrinsic pathway include the inflammatory conditions brought by gastric reflux and hepatitis virus infection, which increase the risk for GC and HCC, respectively. The intrinsic pathway is activated by genetic events that cause neoplasia, for example, the activation of oncogenes, the aberrant gain or loss of chromosome and the inactivation of tumor suppressor genes. Cells transformed in this way produce inflammatory mediators, creating an inflammatory microenvironment even though there is no underlying inflammation condition. In intrinsic pathway, the genetic alteration is the direct cause of both tumorigenesis and inflammation, and the inflammation condition could further enhance tumorigenesis.
Inflammation conditions that are linked to specific GI cancers Bowel cancer CRC is the fourth most common cancer in men and the third in women and the fourth most common cause for cancer-related deaths worldwide. The lifetime risk of CRC is approximately 6% and of colorectal adenoma approximately 50%. The progression from adenoma to colorectal carcinoma usually takes 510 years, characterized by accumulation of genetic
General Introduction
abnormality in colon epithelial cells. The risk of colorectal cancer increases with age. In developed countries, more than 90% of cases are diagnosed in individuals older than 50 years old. Risk is also increased with certain inherited genetic mutations such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), a personal or family history of CRC or polyps, and chronic inflammatory bowel disease. Inflammatory bowel disease (IBD) represents a group of inflammatory conditions of the small intestine and colon. The cause of IBD is not exactly known. There is evidence that the disease is caused by a combination of factors, including intrinsic genetic predisposition, environmental factors and auto-inflammation. Crohns disease (CD) and ulcerative colitis (UC), the main forms of IBD, are different in the location and nature of inflammation. CD can affect any part of the gastrointestinal tract from mouth to anus, although a majority of the cases start in the terminal ileum, whereas UC is restricted to the colon and the rectum. Microscopically, UC is restricted to the mucosa, while CD can affect the whole bowel wall. Although CRC complicating UC and CD only accounts for 12% of all CRC cases in the general population, CRC is a serious consequence of IBD, as it accounts for one in six of all deaths in IBD patients. UC or CD patients have increased risk for CRC. Based on a study carried out in UK, the cumulative risk for developing CRC was 8% at 22 years from onset of symptoms for Crohns colitis and 7% at 20 years from onset of symptoms for ulcerative colitis, representing an 18- and 19-fold increase in cancer risk, respectively, when compared with the background population of matched demographic data.1 Carcinomas complicating CD or UC have been found to have similar pathological features. In a study based on 80 CRC patients complicating CD or UC, cancers in UC and CD occurred at a median of 15 and 18 years after onset of IBD. The tumors were multiple in 11% of CD patients and 12% of UC patients and occurred with the presence of dysplasia in 73% and 79% of CD and UC patients, respectively.2 Histological features of the tumors developed in connection with the two diseases were similar. For example, tumors were predominantly present in chronically inflamed areas of the bowel, suggesting that chronic inflammation, as a common process of the two diseases, is an important underlying mechanism leading to
C. W. Wu and J. Yu
carcinogenesis in IBD. And unlike sporadic CRC where dysplastic lesions arise in one or two focal areas of the colon, the dysplasia in colitic mucosa is usually multifocal. Small bowel cancer is extremely rare compared with cancers of the large bowel. Although few small bowel cancers have been reported in CD, patients with CD show an increased risk of developing this type of cancer. Studies based on European cohorts have revealed that CD patients are 16 to 66 times more likely to develop small bowel cancer than the background population.1,35 The adenoma to carcinoma process of sporadic CRC development and the neoplastic transformation in IBD share many common intrinsic molecular alterations such as the loss of function of adenomatosis polyposis coli (APC) protein, p53 mutations and aberrant methylation of mismatch repair genes; however, there are several differences in the sequence of molecular events between them. For example, APC loss of function, an early event common in sporadic CRC, is less frequent and usually occurs late in the colitis associated dysplasiacarcinoma sequence. On the contrary, p53 mutations, usually a late event in the adenomacarcinoma sequence, occur early in non-dysplastic mucosa of colitis patients. Barretts esophagus and esophageal cancer Esophageal cancer is the ninth most common cancer in the world, of which adenocarcinoma and squamous cell cancer are the major subtypes. Esophageal adenocarcinoma accounts for 5080% of all esophageal cancers, which arises from glandular cells that are present at the junction of the esophagus and stomach. The incidence of esophageal adenocarcinoma is increasing by 10% annually in western countries while that of esophageal squamous carcinoma remains unchanged. Esophagus adenocarcinoma confers a very poor prognosis, even in patients undergoing curative resection, with a mean 5-year survival rate of less than 20%.6 Gastroesophageal reflux disease (GERD) and Barretts esophagus are common precursors to esophageal adenocarcinoma. GERD is a chronic symptom induced by the abnormal reflux in the esophagus, resulting in mucosal damage and esophagitis. Barretts esophagus is an intermediate step in the progression from reflux esophagitis to
General Introduction
esophageal adenocarcinoma, characterized by metaplasia in which the squamous epithelium of the distal esophagus is replaced by columnar epithelium and mucus-secreting goblet cells. Approximately 10% to 20% patients with the chronic reflux develop Barretts esophagus. The incidence of adenocarcinoma in Barretts esophagus with dysplasia is about 30125 times higher than that of the general population.7 Patients with longer segments of Barretts esophagus are more prone to the esophageal adenocarcinoma than those with short segments. Evidence suggests that bile acids in the refluxate play a key role in inducing Barretts esophagus. Increased bile acid exposure can increase esophageal mucosal damage and the severity of Barretts esophagus. The predominant bile acids detected in patients with esophagitis and Barretts esophagus were cholic, taurocholic, and glycocholic acids and a significantly greater proportion of secondary bile acids produced by bacteria such as taurodeoxycholic and deoxycholic acid.8 Bile acid exposure can cause chronic inflammation. Normally, the inflammation of esophageal squamous epithelium heals by the regeneration of new squamous cells. In Barretts esophagus, healing occurs through replacement of damaged cells by columnar epithelium and mucus-secreting goblet cells. These new cells are more resistant to the toxic agents causing the chronic inflammation than the normal esophageal squamous tissue. Persistent inflammation gives rise to increased release of pro-inflammatory mediators including cytokines, chemokines, prostaglandins, and reactive oxygen/nitrogen species. These factors create a microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Viral infections and hepatocellular carcinomas Liver cancer is the fifth most common cancer in men and the eighth in women, and the third leading cause of cancer death in men and the sixth among women. The prognosis of HCC is very poor with a five-year survival rate below 9%. Areas with higher incidence of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections such as Asia and west and central Africa have a higher incidence of HCC. More than 80% of HCC cases occur in developing countries. China alone accounts for nearly 55% of the total cases.
C. W. Wu and J. Yu
Cirrhosis is the major risk factor for progression to HCC. It is initiated from liver fibrosis, which is a wound healing process in response to various kinds of hepatic insults. Fibrosis is characterized by connective tissue production and deposition; it progresses at variable rates depending on the cause of insults, environmental and host factors. Cirrhosis, an advanced stage of liver fibrosis, is accompanied by distortion of the hepatic vasculature, leading to compromised exchange between hepatic sinusoids and hepatocytes. Alcoholic liver disease and hepatitis C are the most common causes of cirrhosis in the Western world, while hepatitis B prevails in most parts of Asia and west and central Africa. HCV infection and nonalcoholic steatohepatitis (NASH) are also important etiology of cirrhosis. HBV and HCV infections are responsible for the majority of hepatocellular carcinomas, accounting for over 80% of all HCC worldwide. There are an estimated 400 million people chronically infected with HBV worldwide, among which up to 40% will develop complications of cirrhosis and HCC. Approximately 7080% of HBV-related HCC occurs in cirrhotic livers, whereas the remainder of the HCC occurs in the absence of cirrhosis. Case-control studies have shown that chronic HBV carriers possess 100-fold increased risk of HCC compared with the general population. HBV infection induces HCC through both intrinsic and extrinsic pathways. For intrinsic pathways, HBV can integrate its DNA into the host genome, causing numerous mutations and chromosome instability. The accumulation of genetic mutation can directly induce tumorigenesis and create a microenvironment that favors tumor growth. Extrinsically, the adaptive immune response, particularly virus-specific killer T cells, contributes to most of the liver injuries associated with HBV infection by killing infected hepatocytes and producing antiviral cytokines. Antigen-nonspecific inflammatory cells can worsen killer T cell-induced immunopathology. Activated platelets at the site of infection also facilitate inflammatory processes by interacting with leukocytes and by secreting chemokines, cytokines and inflammatory mediators. Chronic HCV infection is another major risk factor for the development of HCC. There are approximately 170 million people infected with HCV worldwide, and around 20% of the HCV-infected patients case will
General Introduction
progress to cirrhosis. Once HCV-related cirrhosis is established, HCC develops at an annual rate of 1% to 4% and rates of up to 7% have been reported in Japan. HCC risk was increased 17-fold in HCV-infected patients compared with HCV-negative controls.9 Unlike HBV, HCV, a positive stranded RNA virus that lacks reverse transcriptase activity, is not able to integrate into the host genome. HCV mainly induces HCC through extrinsic pathways by inducing hepatic cell injury and chronic inflammation. Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases caused by the excess fat accumulation in liver, which ranges from simple steatosis to steatohepatitis and finally cirrhosis. NASH is an advanced stage of NAFLD, characterized by a mixed inflammatory lobular infiltrate, liver cell injury, and variable fibrosis. The transformation from simple steatosis to NASH depends on the presence of oxidative stress. During -oxidation of excess fatty acid, reactive oxygen species (ROS) are generated. ROS can lead to elevated lipid peroxides that form adducts with cellular nucleophiles, such as proteins and nucleic acids, resulting in cell damage and the subsequent initiation of an inflammatory response. Chronic inflammatory response can lead to fibrosis and cirrhosis. Clinically, NASH is highly associated with obesity, insulin resistance and type II diabetes. Up to 20% of patients with NASH may progress to cirrhosis, and 40% of cirrhosis patients will die from liver related disease including HCC. In a retrospective cohort study, 420 patients diagnosed with NAFLD in Minnesota were followed up for a mean duration of 7.6 years.10 Twenty-one of them (5%) were diagnosed with cirrhosis, and 2 among them developed HCC. Seven out of the 420 patients died of liver-related disease, one among them died of HCC, as compared with the general population of Minnesota in which liver disease only accounts for less than 1% of all death.10 Once cirrhosis and HCC are established in NASH patients, it becomes difficult to recognize histopathological features of NASH. However, the causative association between NASH and HCC could also be identified through clinical and demographic factors. For example, among HCC patients who had no identifiable cause for chronic liver disease such as alcoholic and viral hepatitis, there is a higher prevalence of obesity and diabetes.11
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Similar to NAFLD, alcoholic liver disease (ALD) encompasses a spectrum of liver injury, ranging from simple steatosis to steatohepatitis and cirrhosis. Continued alcohol use at 40 g per day increased the risk of progression to cirrhosis to 30%, and fibrosis or cirrhosis to 37%.12 A central pathway of generating oxidative stress in alcohol exposed hepatocytes is through the alcohol inducible cytochrome P450 2E1 (CYP2E1), an endoplasmic monooxygenase that oxidizes ethanol. During its catalytic cycle, CYP2E1 readily releases ROS as a result of incomplete transfer of electrons to molecular oxygen and subsequently induces the recruitment of inflammatory response. It has been reported that HCC risk is increased in a linear fashion with daily intake of more than 60 g.9 However, with the concomitant presence of HCV infection, there was an additional 2-fold increase in HCC risk compared with that observed with alcohol use alone. H. pylori infection and gastric cancer GC is the second leading cause of cancer death in men and the fourth among women worldwide. It develops from a stepwise progression from chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and subsequently to cancer. A series of changes in gastric carcinogenesis is often initiated by H. pylori infection. H. pylori is a bacterium that colonizes the stomach. It is not exactly known how H. pylori is transmitted, but the most likely route of spread is from person to person through fecal-oral or oral-oral routes. Possible environmental sources include water contaminated with human waste. In the absence of antibiotic-induced eradication, infection with this gram negative bacterium induces a chronic immune response that persists for the life of the host. Colonization of H. pylori in gastric mucosa is associated with inflammatory cell infiltration into the gastric mucosa, resulting in gastritis. Different H. pylori strains induce varying degrees of gastritis, reflecting their individual abilities to interact with the host. One strain-specific H. pylori constituent that increases cancer risk is the cytotoxin-associated gene (cag) pathogenicity island, a genetic locus that encodes a type IV secretion system that could lead to a loss of cellular polarity. Around 59% of gastric cancer cases in developing countries and 63% of cases in developed countries can be attributed to H. pylori infection. Studies from Asia have shown that individuals who test positive for
Table 1. Inflammatory diseases are able to increase the risk of gastrointestinal cancers. Percentage of cancer cases with the inflammation 1%2% 1%2% Unknown Unknown 80% 80% Unknown Unknown 60% Increased risk of cancer caused by inflammation (by folds) 18 19 1666 30125 515 17 Unknown Unknown >2 General Introduction
Type of GI cancer Colon Cancer Small bowel Cancer Esophageal Cancer Liver Cancer
Rank of mortality rate in male 4 Unknown 5 3
Rank of mortality rate in female 5 Unknown 7 6
Inflammatory disease Crohns disease Ulcerative colitis Crohns disease Barretts esophagus HBV infection HCV infection Alcoholic steatohepatitis Non-alcoholic steatohepatitis H. pylori infection
Cause of inflammation Anto-inflammatory Anto-inflammatory Anto-inflammatory Bile acid HBV HCV Alcohol Metabolic syndromes H. pylori
Gastric Cancer
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H. pylori have at least a two-fold increased risk of developing gastric cancer compared with those who test negative.1314 The association between H. pylori and gastric cancer is especially strong for young patients less than 30 years of age.15 A large prospective study from Japan showed that no individuals who were negative for H. pylori developed gastric cancer during the long-term follow-up;13 Consistently, a study from Taiwan found that all gastric cancers only developed in patients infected with H. pylori.16 These findings suggest that infection with this bacterium plays an important part in gastric-cancer development. However, eradication of H. pylori was not found to be an effective remedy. Clinical evidence showed eradication of H. pylori had not prevented the development of gastric cancer.1719 In fact, most patients may have been infected with H. pylori in childhood and various degrees of mucosal damage had already been established before any intervention. Eradication of the bacterium was also found to result in GERD, esophagitis and weight gain in adults.2022 Conclusion Infections and inflammatory responses are linked to 1520% of all cancer deaths.23 Notably, inflammation conditions in gastrointestinal cancers are important precursors to malignancy. There are many triggers of chronic inflammation that increase cancer risk. Microbial infections play particular prominent roles in GI cancer. Thus, further understanding of the underlying inflammatory mechanisms that lead to the cancer will provide the opportunity of developing anticancer drugs and allow early intervention of cancer formation. References
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17. Leung WK, Lin SR, Ching JY et al. (2004) Factors predicting progression of gastric intestinal metaplasia: Results of a randomised trial on Helicobacter pylori eradication. Gut 53:12449. 18. Sung JJ, Lin SR, Ching JY et al. (2000) Atrophy and intestinal metaplasia one year after cure of H. pylori infection: A prospective, randomized study. Gastroenterology 119:714. 19. Wong BC, Lam SK, Wong WM et al. (2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: A randomized controlled trial. JAMA 291:18794. 20. Azuma T, Suto H, Ito Y et al. (2001) Gastric leptin and Helicobacter pylori infection. Gut 49:3249. 21. Furuta T, Shirai N, Xiao F et al. (2002) Effect of Helicobacter pylori infection and its eradication on nutrition. Aliment Pharmacol Ther 16:799806. 22. Hamada H, Haruma K, Mihara M et al. (2000) High incidence of reflux oesophagitis after eradication therapy for Helicobacter pylori: Impacts of hiatal hernia and corpus gastritis. Aliment Pharmacol Ther 14:72935. 23. Balkwill F, Mantovani A. (2001) Inflammation and cancer: Back to Virchow? Lancet 357:53945.
