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, 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 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.
1. Correa P: Helicobacter pylori as a pathogen and carcinogen. J Physiol
Pharmacol 48(suppl 4):19-24, 1997.
2. Choi PM, Zelig MP: Similarity of colorectal cancer in Crohn’s disease
and ulcerative colitis: Implications for carcinogenesis and prevention. Gut
3. Wiesner RH: Current concepts in primary sclerosing cholangitis. Mayo Clin
Proc 69:969-982, 1994.
4. Risch HA, Howe GR: Pelvic inflammatory disease and the risk of epithelial
ovarian cancer. Cancer Epidemiol Biomarkers Prev 4:447-451, 1995.
5. Ness RB, Cottreau C: Possible role of ovarian epithelial inflammation in
ovarian cancer. J Natl Cancer Inst 91:1459-1467, 1999.
6. Warren JW: Catheter-associated urinary tract infections. Infect Dis Clin
North Am 11:609-622, 1997.
7. Mossman BT, Kamp DW, Weitzman SA: Mechanisms of carcinogenesis and
clinical features of asbestos-associated cancers. Cancer Invest 14:466-480,
8. Deeb ZE, Fox LA, deFries HO: The association of chronic inflammatory
disease in lichen planus with cancer of the oral cavity. Am J Otolaryngol
9. Isla AM: Chronic pancreatitis. Hosp Med 61:386-389, 2000.
10. Rosin MP, Anwar WA, Ward AJ: Inflammation, chromosomal instability, and
cancer: The schistosomiasis model. Cancer Res 54:1929s-1933s, 1994.
11. Chapman RW: Risk factors for biliary tract carcinogenesis. Ann Oncol
12. Pera M, Trastek VF, Pairolero PC, et al: Barrett’s disease:
Pathophysiology of metaplasia and adenocarcinoma. Ann Thorac Surg 56:1191-1197,
13. Hayashi PH, Zeldis JB: Molecular biology of viral hepatitis and
hepatocellular carcinoma. Compr Ther 19:188-196, 1993.
14. Carlson JA, Ambros R, Malfetano J, et al: Vulvar lichen sclerosus and
squamous cell carcinoma: A cohort, case control, and investigational study with
historical perspective; implications for chronic inflammation and sclerosis in
the development of neoplasia. Hum Pathol 29:932-948, 1998.
15. Hogg RP, Ayshford C, Watkinson JC: Parotid duct carcinoma arising in
bilateral chronic sialadenitis. J Laryngol Otol 113:686-688, 1999.
16. Vainio H, Boffetta P: Mechanisms of the combined effect of asbestos and
smoking in the etiology of lung cancer. Scand J Work Environ Health 20:235-242,
17. Thieblemont C, Berger F, Coiffier B: Mucosa-associated lymphoid tissue
lymphomas. Curr Opin Oncol 7:415-420, 1995.
18. Ekbom A, Helmick C, Zack M, et al: Ulcerative colitis and colorectal
cancer. A population-based study. N Engl J Med 323:1228-1233, 1990.
19. Boone CW, Kelloff GJ, Steele VE: Natural history of intraepithelial
neoplasia in humans with implications for cancer chemoprevention strategy.
Cancer Res 52:1651-1659, 1992.
20. Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet
21. Slaga TJ, Lichti U, Hennings H, et al: Effects of tumor promoters and
steroidal anti-inflammatory agents on skin of newborn mice in vivo and in vitro.
J Natl Cancer Inst 60:425-431, 1978.
22. Potter M: Indomethacin inhibition of pristane plasmacytomagenesis in
genetically susceptible inbred mice. Adv Exp Med Biol 469:151-156, 1999.
23. Correa P: Helicobacter pylori and gastric carcinogenesis. Am J Surg
Pathol 19:S37-43, 1995.
24. Parsonnet J: Bacterial infection as a cause of cancer. Environ Health
Perspect 103(suppl 8):263-268, 1995.
25. Konturek PC, Bielanski W, Konturek SJ, et al: Helicobacter pylori
associated gastric pathology. J Physiol Pharmacol 50:695-710, 1999.
26. Tavani A, La Vecchia C, Franceschi S, et al: Medical history and risk of
Hodgkin’s and non-Hodgkin’s lymphomas. Eur J Cancer Prev 9:59-64, 2000.
27. Copie-Bergman C, Niedobitek G, Mangham DC, et al: Epstein-Barr virus in
B-cell lymphomas associated with chronic suppurative inflammation. J Pathol
28. Bornstein J, Rahat MA, Abramovici H: Etiology of cervical cancer: Current
concepts. Obstet Gynecol Surv 50:146-154, 1995.
29. Goedert JJ: The epidemiology of acquired immunodeficiency syndrome
malignancies. Semin Oncol 27:390-401, 2000.
30. Tung BY, Emond MJ, Haggitt RC, et al: Ursodiol use is associated with
lower prevalence of colonic neoplasia in patients with ulcerative colitis and
primary sclerosing cholangitis. Ann Intern Med 134:89-95, 2001.
31. Seitz HK, Poschl G, Simanowski UA: Alcohol and cancer. Recent Dev Alcohol
32. Steenland K, Stayner L: Silica, asbestos, man-made mineral fibers, and
cancer. Cancer Causes Control 8:491-503, 1997.
33. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57-70, 2000.
34. Hennings H, Glick AB, Greenhalgh DA, et al: Critical aspects of
initiation, promotion, and progression in multistage epidermal carcinogenesis.
Proc Soc Exp Biol Med 202:1-8, 1993.
35. Jackson JR, Seed MP, Kircher CH, et al: The codependence of angiogenesis
and chronic inflammation. FASEB J 11:457-465, 1997.
36. Searle J, Kerr JFR, Bishop CJ: Necrosis and apoptosis: Distinct modes of
cell death with fundamentally different significance. Pathol Ann 17:229-259,
37. Savill J, Fadok V: Corpse clearance defines the meaning of cell death.
Nature 407:784-788, 2000.
38. Shacter E, Williams JA, Hinson RM, et al: Oxidative stress interferes
with cancer chemotherapy: Inhibition of lymphoma cell apoptosis and
phagocytosis. Blood 96:307-313, 2000.
39. Hickman JA: Apoptosis induced by anticancer drugs. Cancer Metastasis Rev
40. Prococimer M, Rotter V: Structure and function of p53 in normal cells and
their aberrations in cancer cells: Projection on the hematologic cell lineages.
Blood 84:2391-2411, 1994.
41. Babior BM: Phagocytes and oxidative stress. Am J Med 109:33-44, 2000.
42. Grisham MB, Jourd’heuil D, Wink DA: Review article: Chronic
inflammation and reactive oxygen and nitrogen metabolism—implications in DNA
damage and mutagenesis. Aliment Pharmacol Ther 14(suppl 1):3-9, 2000.
43. Aust AE, Eveleigh JF: Mechanisms of DNA oxidation. Proc Soc Exp Biol Med
44. Marnett LJ: Oxyradicals and DNA damage. Carcinogenesis 21:361-370, 2000.
45. Frenkel K, Chrzan K, Troll W, et al: Radiation-like modification of bases
in DNA exposed to tumor promoter-activated polymorphonuclear leukocytes. Cancer
Res 46:5533-5540, 1986.
46. Schraufstätter I, Hyslop PA, Jackson JH, et al: Oxidant-induced DNA
damage of target cells. J Clin Invest 82:1040-1050, 1988.
47. Szabo C, Ohshima H: DNA damage induced by peroxynitrite: Subsequent
biological effects. Nitric Oxide 1:373-385, 1997.
48. Shacter E, Beecham EJ, Covey JM, et al: Activated neutrophils induce
prolonged DNA damage in neighboring cells. Carcinogenesis 9:2297-2304, 1988.
49. Weitberg AB, Corvese D: Translocation of chromosomes 16 and 18 in oxygen
radical-transformed human lung fibroblasts. Biochem Biophys Res Commun
50. Shacter E: Quantification and significance of protein oxidation in
biological samples. Drug Metab Rev 32:307-326, 2000.
51. Roberts LJ, Morrow JD: The isoprostanes: Novel markers of lipid
peroxidation and potential mediators of oxidant injury. Adv Prostaglandin
Thromboxane Leukot Res 23:219-224, 1995.
52. Wiseman H, Halliwell B: Damage to DNA by reactive oxygen and nitrogen
species: Role in inflammatory disease and progression to cancer. Biochem J
53. Guyton KZ, Spitz DR, Holbrook NJ: Expression of stress response genes
GADD153, c-jun, and heme oxygenase-1 in H2O2- and O2-resistant fibroblasts. Free
Radic Biol Med 20:735-741, 1996.
54. Weitberg AB, Weitzman SA, Clark EP, et al: Effects of antioxidants on
oxidant-induced sister chromatid exchange formation. J Clin Invest 75:1835-1841,
55. Weitzman SA, Weitberg AB, Clark EP, et al: Phagocytes as carcinogens:
Malignant transformation produced by human neutrophils. Science 227:1231-1233,
56. Tamatani T, Turk P, Weitzman S, et al: Tumorigenic conversion of a rat
urothelial cell line by human polymorphonuclear leukocytes activated by
lipopolysaccharide. Jpn J Cancer Res 90:829-836, 1999.
57. Wei H, Frenkel K: In vivo formation of oxidized DNA bases in tumor
promoter-treated mouse skin. Cancer Res 4443:4449, 1991.
58. Ray G, Batra S, Shukla NK, et al: Lipid peroxidation, free radical
production and antioxidant status in breast cancer. Breast Cancer Res Treat
59. Szatrowski TP, Nathan CF: Production of large amounts of hydrogen
peroxide by human tumor cells. Cancer Res 51:794-798, 1991.
60. Mashimo H, Goyal RK: Lessons from genetically engineered animal models.
IV. Nitric oxide synthase gene knockout mice. Am J Physiol 277:G745-750, 1999.
61. Collins AR: Oxidative DNA damage, antioxidants, and cancer. Bioessays
62. Baron JA, Sandler RS: Nonsteroidal anti-inflammatory drugs and cancer
prevention. Annu Rev Med 51:511-523, 2000.
63. Prescott SM, Fitzpatrick FA: Cyclooxygenase-2 and carcinogenesis. Biochim
Biophys Acta 1470:M69-M78, 2000.
64. Smith WL, Garavito RM, DeWitt DL: Prostaglandin endoperoxide H synthases
(cyclooxygenases)-1 and -2. J Biol Chem 271:32768, 1996.
65. Goodwin DC, Landino LM, Marnett LJ: Effects of nitric oxide and nitric
oxide-derived species on prostaglandin endoperoxide synthase and prostaglandin
biosynthesis. FASEB J 13:1121-1136, 1999.
66. Thun MJ, Namboodiri MM, Heath CW Jr: Aspirin use and reduced risk of
fatal colon cancer. N Engl J Med 325:1593-1596, 1991.
67. Waddell WR, Ganser GF, Cerise EJ, et al: Sulindac for polyposis of the
colon. Am J Surg 157:175-179, 1989.
68. Jones MK, Wang H, Peskar BM, et al: Inhibition of angiogenesis by
nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications
for cancer growth and ulcer healing. Nat Med 5:1418-1423, 1999.
69. Oshima M, Dinchuk JE, Kargman SL, et al: Suppression of intestinal
polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2
(COX-2). Cell 87:803-809, 1996.
70. Hinson RM, Williams JA, Shacter E: Elevated interleukin-6 is induced by
prostaglandin E2 in a murine model of inflammation. Possible role of
cyclooxygenase-2. Proc Natl Acad Sci USA 93:4885-4890, 1996.
71. Shacter E, Arzadon GK, Williams J: Elevation of IL-6 in response to a
chronic inflammatory stimulus in mice: Inhibition by indomethacin. Blood
72. Fulton AM: In vivo effects of indomethacin on the growth of murine
mammary tumors. Cancer Res 44:2416-2420, 1984.
73. Vane JR, Botting RM: Anti-inflammatory drugs and their mechanism of
action. Inflamm Res 47:S78-S87, 1998.
74. Aoki Y, Yarchoan R, Braun J, et al: Viral and cellular cytokines in
AIDS-related malignant lymphomatous effusions. Blood 96:1599-1601, 2000.
75. Trentin L, Cerutti A, Zambello R, et al: Interleukin-15 promotes the
growth of leukemic cells of patients with B- cell chronic lymphoproliferative
disorders. Blood 87:3327-3335, 1996.
76. Hilbert DM, Kopf M, Mock BA, et al: Interleukin 6 is essential for in
vivo development of B lineage neoplasms. J Exp Med 182:243-248, 1995.
77. Moore RJ, Owens DM, Stamp G, et al: Mice deficient in tumor necrosis
factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828-831, 1999.
78. Blumberg JB: Considerations of the scientific substantiation for
antioxidant vitamins and beta-carotene in disease prevention. Am J Clin Nutr
79. Sentürker S, Karahalil B, Inal M, et al: Oxidative DNA base damage and
antioxidant enzyme levels in childhood acute lymphoblastic leukemia. FEBS Lett
80. Chinery R, Brockman JA, Peeler MO, et al: Antioxidants enhance the
cytotoxicity of chemotherapeutic agents in colorectal cancer: A p53-independent
induction of p21WAF1/CIP1 via C/EBPb. Nat Med 3:1233-1241, 1997.
81. Conklin KA: Dietary antioxidants during cancer chemotherapy: Impact on
chemotherapeutic effectiveness and development of side effects. Nutr Cancer