The Relationship Between Inflammation and Cancer Is Analogous to That Between Fuel and Fire

Fatigue, fever, depression, confusion, and memory loss are general symptoms that can all indicate inflammation, which itself can often be caused by physical or psychological stress or a common infection such as influenza.[1] Specifically, inflammation is characterized by redness, joint swelling, warmth, pain, stiffness, and loss of function. Inflammation has been linked to most acute and chronic diseases, including neurological, pulmonary, cardiovascular, metabolic, and autoimmune diseases, and-above all-to cancer, the focus of this review.[2-4]

Inflammation's Link to Chronic Disease

Inflammation has been referred to as “the secret killer” and “the fires within us.”[5, 6] But how does one define inflammation? One of the first documented descriptions of inflammation was recorded by the first-century Roman physician Aulus Cornelius Celsus, who defined inflammation as the presence of heat (calor), pain (dolor), redness (rubor), and swelling (tumor). However, it was the nineteenth-century German physician Rudolf Virchow who first linked inflammation to diseases such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma, Alzheimer disease, and cancer.[7] Currently, terminology to describe inflammation of any organ is denoted by adding the suffix “-itis” to the word stem describing the organ.[8] For instance, “bronchitis” means an inflammation of the bronchus, while “colitis” means an inflammation of the colon.[9] As of this writing, over 200 terms containing the suffix “-itis” have been documented.

Patients with conditions such as colitis, gastritis, hepatitis, etc have an increased risk of developing cancer. However, not all types of inflammation result in cancer, as exemplified by arthritis. The exact reason why some inflammatory conditions are linked to cancer while others are not is unclear at present.

The Discovery of a Molecular Link Between Infection and Tumor Regression

Attempts to determine the molecular basis of inflammation date back as far as 1868, when the German physician P. Bruns reported a dramatic regression of tumors in humans who had bacterial infections (for reference, see [10]). In 1891, an American oncologist, William Coley, made use of Bruns’ observations and used extracts from gram-negative bacteria to induce tumor regression; these extracts were later referred to as “Coley’s toxins.”[11] In 1944, M. Shear, a researcher at the National Institutes of Health, was the first to isolate lipopolysaccharide (LPS) as the active component of the gram-negative bacteria used by Coley, and the first to demonstrate LPS’s ability to reduce tumors in animals.[12] He named this LPS-induced soluble factor “tumor necrosis serum” (TNS).

The Many Roles of TNF-α

Eventually, TNS was renamed as “tumor necrosis factor” (TNF). In 1984, our group was the first to purify, sequence, and clone the cDNA for this factor, which we named TNF-α.[13,14]

Subsequently, we showed that while TNF-α induced apoptosis in some cells, it induced proliferation in other cell types.[15] Thus, although TNF-α was discovered as an antitumor agent, TNF-α was also the first known apoptosis-inducing cytokine, and was shown to have the ability to induce tumor regression in both preclinical and clinical models of human cancers. Within 2 years of its discovery, TNF-α was identified as the primary mediator of inflammation.[16] By 1987, it had become clear that TNF-α was a growth factor in breast and ovarian cancers and certain types of leukemia and lymphoma.[17-19] In fact, TNF-α that has been targeted to certain types of tumors is being studied in clinical trials in Europe as of this writing.[20]

Today TNF-α is known to be an integral component of the immune system, and while produced primarily by macrophages, it is required for the development and proliferation of both B cells and T cells.[11] Thus, TNF-α has been found to be critical for protection against different types of infection, as indicated by the susceptibility to infection of patients who undergo anti-TNF therapy.[21-23] Similarly, animals with genetic deletion of TNF-α or its receptor are vulnerable to infections.[24-27]

FIGURE

The mitochondria play a central role in both inflammation and tumorigenesis

A Double-Edged Sword

When confined to the immune system, TNF-α is therapeutic. However, when expressed in organs outside the immune system, this cytokine causes serious inflammation with pathologic consequences. Thus, TNF-α is a double-edged sword.

Like TNF-α, inflammation, too, is a double-edged sword. TNF-mediated inflammation in the immune system has therapeutic effects, but this type of inflammation is acute or “short-term” and is less likely to do any permanent harm. It is chronic or “long-term” inflammation, which is usually low-level and can persist for as long as 20 to 30 years, that is more likely to damage the affected organ and that is more likely to lead to a chronic disease such as cancer.

The Role of NFκB in Immunity, Inflammation, and Cancer

The way in which TNF-α mediates inflammation has become highly evident in the last quarter of a century.[8] Soon after TNF-α was discovered, Sen and Baltimore described the discovery of a transcription factor that was present in the nucleus of B cells and that was binding to the promoter of the immunoglobulin kappa chain; they named this transcription factor NFκB.[28] In 1989, TNF-α was found to be the most potent activator of NFκB.[29] Today, NFκB is acknowledged to be universally present in every cell type in the body; it is usually found in the cytoplasm in its inactive state and has been conserved in all species all the way from Drosophila to man. When activated, NFκB controls the expression of over 500 different gene products, most of which have been linked to inflammation, cellular transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis.[30]

NFκB is activated not only by TNF-α but also by most factors that have been linked to tumorigenesis, including reactive oxygen species (ROS), hydrogen peroxide, stress (psychological, physical, chemical, or mechanical), dietary agents implicated in cancer, cigarette smoke, tobacco, environmental pollutants, asbestos, alcohol, radiation, and various cancer-causing viruses and bacteria, such as Helicobacter pylori. Thus, NFκB is one of the major sensors of carcinogenic agents. Furthermore, NFκB controls the expression of another transcription factor, STAT3, through the expression of interleukin (IL)-6.

Constitutively activated NFκB has not been encountered in cells other than those from the immune system, but it has been observed in almost all tumor cell types. In most cases, tumor cells are addicted to NFκB, and these cells’ survival is dependent on activated NFκB.[2,31,32] Most chemotherapeutic agents and gamma radiation, both of which are commonly used for cancer treatment, invariably activate NFκB and mediate chemoresistance and radioresistance. Thus, downmodulation of NFκB can be justified as a suitable target for chemosensitization and radiosensitization.

The presence of activated NFκB has been shown to be a predictor of response to chemotherapy in patients with breast cancer [33,34] and in patients with esophageal cancer.[35,36] In addition, both NFκB and NFκB-regulated inflammatory gene products have been associated with overall survival in patients with virtually all types of cancer.[37] Thus, therapeutic agents that can downmodulate NFκB can also downmodulate inflammation and thereby downmodulate the overall process of tumorigenesis. NFκB inhibitors thus have potential for both prevention and treatment of cancer.[38-40]

However, like TNF-α, NFκB is a double-edged sword. Although NFκB is critical for proper function of the immune system, its dysregulation in various organs leads to a pathologic response. The role of NFκB in inflammation is further evident from well-known anti-inflammatory agents, including corticosteroids and nonsteroidal anti-inflammatory agents such as aspirin and celecoxib, all of which downregulate NFκB activation.[41,42] In addition, our laboratory and other researchers have described numerous novel inhibitors of NFκB-from dietary agents to traditional medicines-that can suppress NFκB activation safely and thus have potential for both prevention and treatment of cancer.[43-48] This evidence clearly shows that inflammation is closely linked to cancer.

Inflammation and Mutated Genes:Pouring Fuel on the Fire

Although cancer is a disease caused by mutations in various genes, the component that seems to be required for the mutated cells to survive, proliferate, and migrate to other organs is chronic inflammation. Thus, the relationship between mutated genes and inflammation is analogous to the relationship between “fire and fuel,” with mutated genes the “fire” and inflammation the “fuel” needed to induce tumorigenesis/carcinogenesis.

Mitochondria and Tumorigenesis

The current article by Kamp et al further explores the link between chronic inflammation and cancer, specifically focusing on the role of mitochondria, the “power house” of the cell.[4] Perhaps one of the first pieces of evidence that mitochondria have any role in cancer comes from Otto Warburg, a researcher who studied glucose metabolism in cancer cells and who showed that respiration was impaired in tumor cells.[49] Mitochondria’s involvement in cancer is hardly surprising, since more than 80% of the ROS produced by the cell are from mitochondria, and since ROS play a critical role in the activation of NFκB and the expression of inflammatory cytokines and enzymes. Furthermore, NFκB has been localized in mitochondria and plays an important role in the synthesis of proteins involved in tumorigenesis.[50,51] The authors also discuss the roles of K-Ras and c-Myc, both of which are closely linked to NFκB activation.[52-54] Kamp et al also note that 43% of patients with ulcerative colitis will develop colon cancer within 25 to 35 years.

Countering Chronic Inflammation to Prevent and Treat Cancer: The Importance of Agents With Long-Term Safety

The studies discussed in this review suggest that chronic diseases such as cancer are caused by chronic inflammation and require chronic treatment. No agent currently is approved by the FDA that can be safely administered long-term. However, many natural agents derived from spices, vegetables, fruits, legumes, and cereals, as previously described by us and others, can suppress NFκB–regulated inflammation and likely can be administered safely long-term, by virtue of their history of routine consumption. Thus, these agents should have the potential to both prevent and treat cancer.[40,45-47]

For instance, curcumin, derived from the yellow spice turmeric (Curcuma longa), which has been used for centuries, has been found to suppress inflammation through inhibition of NFκB and STAT3 and has been associated with both cancer prevention and treatment.[55,56] Curcumin can be consumed long-term with minimal side effects and no known toxicity. A recent placebo-controlled study in which curcumin was compared with the cholesterol-lowering drug atorvastatin revealed that curcumin at 150 mg/twice a day for 6 weeks downregulated endothelin-1, TNF-α, IL-1, IL-6, and malondialdehyde, a lipid peroxidation product.[57] Another recent study of 123 patients with colorectal cancer showed that curcumin downmodulated TNF expression, prevented cancer-associated weight loss, and induced apoptosis in tumors through the upregulation of p53 and bax; it also induced downregulation of bcl-2 in the tumor tissue.[58] Although bioavailability of curcumin is perceived to be a problem, as little as 300 mg taken twice a day for 15 days was found to be effective in these studies, whereas no such change in inflammatory biomarkers was observed in patients in the placebo arm.[50] Another recent study, a phase IIa clinical trial, examined the ability of curcumin to prevent colorectal neoplasia.[59] A significant 40% reduction in aberrant crypt foci number was observed with the 4-g dose (P < .005). Besides curcumin, literally hundreds of other such dietary agents have been identified that can control inflammation; however, clinical experience with these agents is limited. All this proves the wisdom of Hippocrates, the Greek physician who proclaimed 25 centuries ago, “Let food be thy medicine, and medicine be thy food.”

Thus it is clear that inflammation plays a major role in cancer growth-but also in cancer prevention and treatment. The regulation of dysregulated inflammation has huge potential. The source of this regulation lies not in the “Pharma” market but in the “Farmers market.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES:

1. Hasegawa S, Matsushige T, Inoue H, et al. Serum and cerebrospinal fluid cytokine profile of patients with 2009 pandemic H1N1 influenza virus-associated encephalopathy. Cytokine. 2011.

2. Prasad S, Ravindran J, Aggarwal BB. NF-kappaB and cancer: how intimate is this relationship? Mol Cell Biochem. 2010;336:25-37.

3. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res. 2009;15:425-30.

4. Kamp DW, Shacter E, Weitzman SA. Chronic inflammation and cancer: the role of the mitochondria. Oncloogy. 2011;25:400-13.

5. Gorman C, Park A, Dell K. The fires within. Time. 2004;163.

6. Stipp D. The secret killer. Fortune. 2003;148:108-10, 12, 14.

7. Heidland A, Klassen A, Rutkowski P, Bahner U. The contribution of Rudolf

Virchow to the concept of inflammation: what is still of importance? J Nephrol. 2006;19 Suppl 10:S102-9.

8. Pacak MG, Norton LM, Dunham GS. Morphosemantic analysis of -ITIS forms in medical language. Methods Inf Med. 1980;19:99-105.

9. Aggarwal BB, Shishodia S, Sandur SK, et al. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72:1605-21.

10. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745-56.

11. Coley WB. II. Contribution to the knowledge of sarcoma. Ann Surg. 1891;14:199-220.

12. Seligman AM, Shear MJ, et al. Chemical alteration of polysaccharide from Serratia marcescens; tumor-necrotizing polysaccharide tagged with radioactive iodine. J Natl Cancer Inst. 1948;9:13-8.

13. Pennica D, Nedwin GE, Hayflick JS, et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984;312:724-9.

14. Aggarwal BB, Kohr WJ, Hass PE, et al. Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem. 1985;260:2345-54.

15. Sugarman BJ, Aggarwal BB, Hass PE, et al. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985;230:943-5.

16. Nawroth PP, Bank I, Handley D, et al. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986;163:1363-75.

17. Spriggs D, Imamura K, Rodriguez C, et al. Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line. Proc Natl Acad Sci U S A. 1987;84:6563-6.

18. Digel W, Stefanic M, Schoniger W, et al. Tumor necrosis factor induces proliferation of neoplastic B cells from chronic lymphocytic leukemia. Blood. 1989;73:1242-6.

19. Balkwill F, Joffroy C. TNF: a tumor-suppressing factor or a tumor-promoting factor? Future Oncol. 2010;6:1833-6.

20. Gregorc V, Zucali PA, Santoro A, et al. Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol. 2010;28:2604-11.

21. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345:1098-104.

22. Bruns H, Meinken C, Schauenberg P, et al. Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobacterium tuberculosis in humans. J Clin Invest. 2009;119:1167-77.

23. Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55.

24. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med. 1996;184:1397-411.

25. Marino MW, Dunn A, Grail D, et al. Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A. 1997;94:8093-8.

26. Rothe J, Lesslauer W, Lotscher H, et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993;364:798-802.

27. Pfeffer K, Matsuyama T, Kundig TM, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993;73:457-67.

28. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986;47:921-8.

29. Duh EJ, Maury WJ, Folks TM, et al. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989;86:5974-8.

30. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004;6:203-8.

31. Chaturvedi MM, Sung B, Yadav VR, et al. NF-kappaB addiction and its role in cancer: ‘one size does not fit all’. Oncogene. 2010.

32. Sethi G, Sung B, Aggarwal BB. Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med (Maywood). 2008;233:21-31.

33. Montagut C, Tusquets I, Ferrer B, et al. Activation of nuclear factor-kappa B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients. Endocr Relat Cancer. 2006;13:607-16.

34. Buchholz TA, Garg AK, Chakravarti N, et al. The nuclear transcription factor kappaB/bcl-2 pathway correlates with pathologic complete response to doxorubicin-based neoadjuvant chemotherapy in human breast cancer. Clin Cancer Res. 2005;11:8398-402.

35. Izzo JG, Correa AM, Wu TT, et al. Pretherapy nuclear factor-kappaB status, chemoradiation resistance, and metastatic progression in esophageal carcinoma. Mol Cancer Ther. 2006;5:2844-50.

36. Izzo JG, Malhotra U, Wu TT, et al. Association of activated transcription factor nuclear factor kappab with chemoradiation resistance and poor outcome in esophageal carcinoma. J Clin Oncol. 2006;24:748-54.

37. Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol. 2009;9:351-69.

38. Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010;29:405-34.

39. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799:775-87.

40. Anand P, Kunnumakkara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008;25:2097-116.

41. Shishodia S, Aggarwal BB. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9. Cancer Res. 2004;64:5004-12.

42. Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene. 2004;23:9247-58.

43. Gullett NP, Ruhul Amin AR, Bayraktar S, et al. Cancer prevention with natural compounds. Semin Oncol. 2010;37:258-81.

44. Prasad S, Phromnoi K, Yadav VR, et al. Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Med. 2010;76:1044-63.

45. Aggarwal BB, Van Kuiken ME, Iyer LH, et al. Molecular targets of nutraceuticals derived from dietary spices: potential role in suppression of inflammation and tumorigenesis. Exp Biol Med (Maywood). 2009;234:825-49.

46. Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al. Potential of spice-derived phytochemicals for cancer prevention. Planta Med. 2008;74:1560-9.

47. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 2006;71:1397-421.

48. Aggarwal BB, Ichikawa H, Garodia P, et al. From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer. Expert Opin Ther Targets. 2006;10:87-118.

49. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269-70.

50. Cogswell PC, Kashatus DF, Keifer JA, et al. NF-kappa B and I kappa B alpha are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-kappa B. J Biol Chem. 2003;278:2963-8.

51. Zamora M, Merono C, Vinas O, Mampel T. Recruitment of NF-kappaB into mitochondria is involved in adenine nucleotide translocase 1 (ANT1)-induced apoptosis. J Biol Chem. 2004;279:38415-23.

52. Basseres DS, Ebbs A, Levantini E, Baldwin AS. Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res. 2010;70:3537-46.

53. Staudt LM. Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol. 2010;2:a000109.

54. Wang JC, Bennett MR. Nuclear factor-{kappa}B-mediated regulation of telomerase: the Myc link. Arterioscler Thromb Vasc Biol. 2010;30:2327-8.

55. Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci. 2009;30:85-94.

56. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23:363-98.

57. Usharani P, Mateen AA, Naidu MU, et al. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R D. 2008;9:243-50.

58. He ZY, Shi CB, Wen H, et al. Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer nvest. 2011;29:208-13.

59. Carroll RE, Benya RV, Turgeon DK, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 2011;4:354-64.