ABSTRACT: A substantial body of evidence supports the conclusion that chronic inflammation can predispose an individual to cancer, as demonstrated by the association between chronic inflammatory bowel diseases and the increased risk of colon carcinoma. Chronic inflammation is caused by a variety of factors, including bacterial, viral, and parasitic infections, chemical irritants, and nondigestible particles. The longer the inflammation persists, the higher the risk of associated carcinogenesis. This review describes some of the underlying causes of the association between chronic inflammation and cancer. Inflammatory mediators contribute to neoplasia by inducing proneoplastic mutations, adaptive responses, resistance to apoptosis, and environmental changes such as stimulation of angiogenesis. All these changes confer a survival advantage to a susceptible cell. In this article, we discuss the contribution of reactive oxygen and nitrogen intermediates, prostaglandins, and inflammatory cytokines to carcinogenesis. A thorough understanding of the molecular basis of inflammation-associated neoplasia and progression can lead to novel approaches to the prevention and treatment of cancer.
Chronic inflammation may be a causative factor in a variety of cancers. In general, the longer the inflammation persists, the higher the risk of cancer. Hence, acute inflammation, such as occurs in response to a transient infection, is not regarded as a risk factor for the development of neoplasia, although many of the same molecular mediators are generated in both acute and chronic inflammation. In general, inflammatory leukocytes such as neutrophils, monocytes, macrophages, and eosinophils provide the soluble factors that are thought to mediate the development of inflammation-associated cancer, although other cells, including the cancer cells themselves, also participate.
Inflammatory mediators include metabolites of arachidonic acid, cytokines, chemokines, and free radicals. Chronic exposure to these mediators leads to increased cell proliferation, mutagenesis, oncogene activation, and angiogenesis. The ultimate result is the proliferation of cells that have lost normal growth control. Animal models provide experimental evidence that chronic inflammation can promote cancer and further insights into possible mechanisms.
This review will summarize the clinical association between chronic inflammation and cancer and will describe the inflammatory factors and pathways that are thought to be proneoplastic. Emphasis will be placed on examining the role of the reactive oxygen and nitrogen intermediates, cytokines, and prostaglandins.
Inflammatory Conditions That Predispose to Cancer
A wide array of chronic inflammatory conditions predispose susceptible cells to neoplastic transformation (Table 1).[1-17] Most of the resulting tumors are of epithelial cell origin (carcinomas). The most widely studied and best established of these links are colon carcinoma associated with inflammatory bowel disease (chronic ulcerative colitis and Crohn’s disease), esophageal adenocarcinoma associated with reflux esophagitis (Barrett’s esophagus), hepatitis predisposing to liver cancer, schistosomiasis causing an increased risk of bladder and colon carcinomas, and chronic Helicobacter infection leading to cancer of the stomach. Some increase in the incidence of lymphoma is also seen, particularly mucosa-associated lymphoid tissue (MALT) lymphoma.
Inflammatory Bowel Disease and Colon Carcinogenesis
Much of our understanding of the association between chronic inflammation and cancer is illustrated through inflammatory bowel disease and colon carcinogenesis. Patients with either chronic ulcerative colitis or Crohn’s disease have a five- to sevenfold increased risk of developing colorectal carcinoma. It is generally thought that the colitis must persist for at least 8 years to significantly increase the risk of cancer. Neoplasia generally appears after a median duration of approximately 15 years. Increased cancer incidence is associated with increased duration of the inflammation.
Like other forms of cancer, colon carcinogenesis is a multistage process. It begins with focal proliferation of dysplastic cells, the formation of benign adenomatous polyps, and potential progression to malignant adenocarcinomas. Mutations in oncogenes and tumor-suppressor genes (p53, APC, and Ki-ras) are found in a high percentage of colon cancers. The molecular nature of the mutations differs in colon cancers associated with chronic colitis compared to sporadic and familial colon carcinoma, suggesting different mechanisms of mutagenesis. The cancers that develop are found predominantly at the sites of the inflammation and not at distant sites. Chronic intake of anti-inflammatory drugs decreases the incidence of colon carcinogenesis associated with inflammatory bowel diseases (see below).
Animal models demonstrate experimentally that chronic inflammation predisposes to the development of various forms of cancer. For example, marmosets have a high incidence of spontaneous colitis and a high incidence of colon cancer as well. Skin cancer is induced by ad-ministration of carcinogens such as dimethylbenzanthracine (DMBA) followed by repeated administration of tumor promoters such as phorbol myristate acetate (PMA) or benzoyl peroxide(Drug information on benzoyl peroxide), which induce inflammation and the production of various inflammatory mediators. Intraperitoneal introduction of mineral oils (eg, pristane) or plastic discs into BALB/c mice promotes the formation of chronic granulomatous tissue and the development of plasmacytomas.
In these animal models, the tumors generally arise in the inflammatory tissue, indicating that local inflammatory mediators are responsible for their development. In some cases, there is strong evidence suggesting a genetic basis for the susceptibility to tumor development. For example, in the mouse plasmacytoma model, BALB/c mice are uniquely susceptible to developing plasma cell tumors in response to pristane, whereas most other strains are not. Similarly, SENCAR mice are uniquely susceptible to developing skin tumors in response to DMBA and PMA. These findings provide a basis for identifying critical genes and factors that contribute to tumor development and may explain why, for example, some individuals with chronic inflammatory conditions and carcinogen exposure (eg, smokers) develop cancer while others do not.
As shown in Table 1, the types of chronic inflammation that lead to cancer are varied. In some cases, the progenitors of the inflammation are known. These include chronic bacterial and parasitic infections, chemical irritants, and nondigestible particles. In other cases, the underlying cause of the chronic inflammation is unknown. This is true for inflammatory bowel disease, sialadenitis, and lichen sclerosis. Some of the known chronic inflammatory agents will be described below. Of these, parasitic infections are perhaps the best described. It seems that any parasitic infection that persists or recurs over many years can predispose to cancer. Thus, bacterial, viral, and parasitic infections can all lead to cancer if left unchecked.
The strongest association between chronic bacterial infection and the development of cancer involves the organism Helicobacter pylori, which is associated with at least a twofold increased risk of adenocarcinoma of the stomach.[23,24] In addition, H pylori infection is thought to increase the incidence of MALT lymphoma. Strong experimental evidence that Helicobacter infection is carcinogenic comes from studies showing that gerbils infected with H pylori develop active chronic gastritis followed by a high incidence of gastric adenocarcinoma. Helicobacter infection in humans is always accompanied by mucosal inflammation (gastritis) with an influx of lymphocytes, plasma cells, and neutrophils. The robust immune response to H pylori generally fails to clear the infection, thus resulting in a chronic inflammatory response thought to be a key element of the carcinogenic activity of the bacterium.
Unless treated, H pylori infection and the associated gastritis persist for decades. Eradication of H pylori infection with antibiotics may also eliminate the excess risk for cancer, but this has not yet been established.
Several parasitic infections are known to increase the risk of cancer. Schistosomiasis is prevalent primarily in Third World countries and is difficult to treat because contaminated water supplies lead to reinfection. Chronic schistosomiasis induces cystitis and fibrosis and increases the incidence of carcinoma of the bladder, liver, and rectum, and follicular lymphoma of the spleen, with different strains of the parasites infecting specific organs and leading to the various cancers. Liver flukes (Opisthorchis and Clonarchis), introduced by eating raw fish, infect the bile duct and lead to chronic cholangitis associated with an increased incidence of cholangiocarcinoma. Chronic infection and inflammatory diseases may also contribute to the development of Hodgkin’s disease and non-Hodgkin’s lymphoma.
Many different viruses cause an increased incidence of cancer. Those most commonly associated with chronic inflammation are the hepatitis B and C viruses, which lead to chronic active hepatitis and hepatocellular carcinoma. Epstein-Barr virus (EBV) is associated with B-cell non-Hodgkin’s lymphoma, and may contain a chronic inflammatory component. Other viral infections can also increase the incidence of cancer, but the role of inflammatory mediators is less clear. For example, the human papillomavirus, herpes simplex virus 2, and cytomegalovirus have been implicated in cervical and other carcinomas. Among RNA retroviruses, the human immunodeficiency virus (HIV) predisposes to the development of non-Hodgkin’s lymphoma, squamous cell carcinomas, and Kaposi’s sarcoma, while the human T-cell lymphoma virus causes adult T-cell leukemia.
Unlike the other parasitic infections described here, viruses implicated in inducing neoplasia directly infect the cells that ultimately undergo neoplastic transformation. Hence, it is difficult to determine whether these agents act by causing a chronic inflammatory condition, by directly transforming the cells that they infect, or both. Most of these viruses induce chronic increased proliferation of the infected cells, thus predisposing to neoplastic transformation (see below). For example, EBV causes sustained proliferation of peripheral B lymphocytes, but when coupled with a secondary mutation can result in malignant transformation, such as occurs with the chromosomal translocations that activate the c-myc oncogene in Burkitt’s lymphoma. The hepatitis viruses are thought to give rise to hepatocellular carcinoma by causing liver damage and regeneration together with the generation of secondary inflammatory mediators.
Noninfectious Causes of Chronic Inflammation
Various noninfectious agents also cause chronic inflammation associated with an increased risk of cancer. For example, esophageal reflux causes chronic exposure of the esophageal epidermis to irritation by gastric acids. This leads to reflux esophagitis, or Barrett’s esophagus, and subsequent development of esophageal carcinoma.
Excess fecal bile acids in patients with primary sclerosing cholangitis and ulcerative colitis are associated with an increased risk of colorectal carcinoma. A recent publication demonstrated that ursodiol (Actigall), a drug that reduces the colonic levels of deoxycholate and other bile acids (used to treat cholangitis), significantly reduces the incidence of neoplasia. Chronic irritation of the liver by alcohol(Drug information on alcohol) causes cirrhosis and hepatocellular carcinoma.
Nondigestible agents such as asbestos, coal, and silica dust lead to chronic inflammation in the lung because of the inability of the immune system to remove the substances. Such sterile inflammations increase the incidence of epithelial cancers including mesothelioma and lung carcinoma. Experimental evidence that chronic sterile inflammation can cause cancer comes from studies in BALB/c mice that received intraperitoneal administration of nondigestible, nongenotoxic mineral oils or plastic disks. The mice developed a high incidence of B lymphocytic (plasma cell) tumors but no epithelial cancers.
Cigarette smoke is a complex proneoplastic agent that may act, in part, by inducing a chronic inflammatory condition. Smoking not only causes chronic bronchitis, but also delivers an array of genotoxic carcinogens (eg, nitrosamines, peroxides) into the lungs. Hence, at present, it is unclear to what degree chronic bronchitis, mutagens in the smoke, and other factors contribute to the high incidence of lung carcinoma among smokers.
There are limitations, however, to using epidemiology to understand the causes of cancer. Definitive evidence that chronic inflammation predisposes to cancer requires identification of the causative inflammatory mediators as well as the agents that prevent neoplastic transformation through inhibition of the inflammatory process. The remainder of this review will focus on the mechanisms whereby inflammatory mediators promote neoplastic transformation.