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. 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. Currently, terminology to describe inflammation of any organ is denoted by adding the suffix “-itis” to the word stem describing the organ. For instance, “bronchitis” means an inflammation of the bronchus, while “colitis” means an inflammation of the colon. 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 ). 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.” 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. 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. 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. 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.
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. 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]
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. 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. In 1989, TNF-α was found to be the most potent activator of NFκB. 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.
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(Drug information on hydrogen peroxide), stress (psychological, physical, chemical, or mechanical), dietary agents implicated in cancer, cigarette smoke, tobacco, environmental pollutants, asbestos, alcohol(Drug information on 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. 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(Drug information on 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. 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. 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(Drug information on 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. 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. 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. Another recent study, a phase IIa clinical trial, examined the ability of curcumin to prevent colorectal neoplasia. 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.