An Aspirin for your Cancer?
Can tumors—which can originate from, and often resemble, chronically inflamed tissue—be curtailed using familiar anti-inflammatory agents, without their side effects?
What if taking aspirin could reduce your risk of cancer? Researchers have debated the relationship between inflammation and cancer for many years, but recent studies have reignited the discussion with evidence that taking aspirin daily for 5 years or longer can protect against death from colorectal and other solid cancers. If this observation indeed holds true, and aspirin can stave off cancer or reduce the risk of recurrence, this familiar, age-old drug could offer a tantalizingly simple treatment.
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1 Earlier studies had shown that daily use of aspirin and other NSAIDs over extended periods reduced the risk of colorectal cancer or polyp recurrence, but no clear evidence was previously available, at least in humans, that aspirin might also reduce the risk of other cancers. In the new study, the benefit of aspirin use was apparent after at least five years of treatment. In trials in which the patients had been taking aspirin for more than 7.5 years, the 20-year risk of cancer death (from the initiation of the trials) was reduced by approximately 30 percent for all solid cancers and by 60 percent for gastrointestinal cancers. For lung and esophageal cancer, the benefit was confined to subtypes of those cancers that originated in glandular tissue (adenocarcinomas). For colorectal cancer, the effect was high for cancer in the proximal colon but not in the distal colon.
These data clearly point to the importance of anti-inflammatory drugs in preventing the initiation and progression of both gastrointestinal and other solid organ cancers (including lung and prostate), and suggest that inflammation may be an underlying cause of cancer even in tumor types that had not been traditionally thought to originate within chronically inflamed tissues.
Although the role of inflammation in favoring carcinogenesis has generated much interest in the last 10–15 years, the Greek physician Claudius Galenus observed some similarity between cancer and inflammation almost 2 thousand years ago. Galenus originally used Hippocrates’s term “cancer” specifically to describe certain inflammatory tumors of the breast in which superficial veins appeared swollen and radiated, somewhat like the claws of a crab. Later the name was extended to include all malignant and infiltrating growths. In 1863 Rudolf Virchow noted white blood cells or leukocytes in neoplastic tissues and made a connection between inflammation and cancer. He suggested that the “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic inflammation. A seminal observation was made more than a century later, when Harold Dvorak of Harvard University noted that inflammation and cancer share some basic developmental mechanisms (angiogenesis) and tissue-infiltrating cells (lymphocytes, macrophages, and mast cells), and that tumors act like “wounds that do not heal.”
Chronic inflammation can affect all phases of carcinogenesis, from favoring the initial genetic alterations that drive cancer formation, to acting as a tumor promoter by establishing conditions in the surrounding tissues that allow the tumor to progress and metastasize, and even triggering immunosuppressive mechanisms that prevent an effective immune response against the tumors.
In 2004 Robert Bass Jr. at the The University of Texas M. D. Anderson Cancer Center and colleagues showed for the first time that the cancer gene RAS also plays an important role in inflammation.2 Recent studies furthered this research, revealing that such genes often have dual roles. Many genes that are known to play a role in cancer when they are abnormally activated—the oncogenes RAS, RET, BRAF, SRC, and MYC—appear to play a role in inflammation as well. These genes turn on the inflammatory pathway within the cell, as well as activating inflammation outside the cell, by recruiting and initiate inflammatory cells that create an environment which reduces anticancer immune cell defenses.3 Interestingly, by way of epigenetic changes, continued activation or overexpression of oncogenes may not always be required for maintaining this pro-inflammatory loop: transient activation of the SRC oncoprotein induces an epigenetic switch that uses microRNA regulation to stably maintain the production of IL-6, a key inflammatory cytokine.4 Severe DNA damage, such as double-stranded breaks, activates the ataxia telangiectasia-mutated (ATM) enzyme, a kinase that repairs DNA but also turns on the secretion of pro-inflammatory factors. These same factors go on to create conditions that promote an oncogenic growth of cells with double-strand breaks, thereby maintaining the production of proinflammatory factors through a positive feedback loop.5
A number of innate immune receptors, like the numerous members of the Toll-like receptor (TLR) family and other pattern-recognition receptors (PRRs), activate inflammatory signals within the cell when they encounter signs of bacterial or viral infection such as nucleic acids and pieces of bacterial cell wall or flagellum. Recent evidence has shown that the pathways that are activated by these innate immune receptors also activate functions—such as cell proliferation, differentiation, and cell death—which can predispose a cell to cancer.7
These receptors activate the cell’s first-responder mechanism, which turns on major transcription factors that quickly activate genes to prepare cells for the onslaught of damage. The transcription factors, NF-κB, STAT3, and the adaptor protein MyD88—each of them key to the innate inflammatory response—are also proving to be essential in certain kinds of cancers.
NF-κB was first discovered by David Baltimore in 1986 as a protein involved in immunity and was subsequently shown to trigger innate inflammation.8 Today, research is beginning to indicate that its expression is also required for oncogenesis in many tissues.9 NF-κB activates genes involved in regulating the cell cycle, angiogenesis, and cell survival, as well as genes encoding pro-inflammatory cytokines, chemokines, and proteases—processes that can play major roles in cancer initiation and progression when not properly kept in check.
STAT3 is another major transcription factor involved in immunity and inflammation. It is also overexpressed and phosphorylated in most types of cancer. STAT3 contributes to tumor cells’ survival, proliferation, and dissemination by controlling the expression of several cell-cycle genes and of the proto-oncogene c-MYC. STAT3 also favors survival of malignant cells by preventing apoptosis, in part by transcriptional downregulation of p53, and by controlling pro-angiogenic and metastatic factors such as VEGF and metalloproteases.9
In skin cancers, expression of STAT3 in epithelial cells is required for the initiation of cancer formation, suggesting that inflammation is a necessary component of carcinogenesis in this tissue. Paradoxically, when turned on in cancer cells, STAT3 activates expression of chemokines that promote inflammation and immunity. However, when it is activated in immune cells, the same pathway initiates anti-inflammatory or immunosuppressive signals that shield the tumor from immune attack. These contrasting activities of STAT3 favor tumor growth because the activated immune cells that are recruited to the site of inflammation provide factors for angiogenesis and rebuilding of the extracellular matrix, both of which favor tumor growth, while the strong inflammatory and immune responses that are associated with antitumor and anti-angiogenic effects are prevented.9
Both NF-κB and STAT3 are activated and regulated in their activities by a number of mechanisms and regulatory molecules. One such mechanism is controlled by the signaling adaptor protein MyD88, which is required for the downstream signaling of most of the Toll-like receptors (TLRs) and the interleukin-1 (IL-1) family of pro-inflammatory cytokines. MyD88 is central for the activation of NF-κB and some of the other most important molecular pathways for innate inflammation.
Recently, MyD88 has been reported to have an important role in tumor promotion. Mice with a disruption in the MyD88 gene exhibited fewer cases of several types of cancer, such as skin and liver cancers, as well as sarcomas induced by chemical treatments. Furthermore, reduced colon tumor growth was observed in MyD88-deficient mice subjected to multiple cancer-initiating agents. In many of these experimental models, the protumorigenic role of MyD88 signaling has been attributed, in part, to its induction of STAT3 signaling downstream of TLRs or IL-1 receptors.10
These data in experimental animals have recently been validated in human studies. In order to continually grow in humans, a subtype of B-cell lymphoma is dependent on a mutation in the MyD88 gene that results in a hyperactive molecule. The overexpressed MyD88 in this cancer promotes cell survival by spontaneously assembling an MyD88 complex, resulting in increased NF-κB signaling, activation of STAT3, and secretion of other inflammatory cytokines.11 These findings fully support the concept that innate-receptor signaling in tumor cells regulates both intrinsic inflammation and the cancerous phenotype of the cells. In an interesting exception, MyD88 is protective against colon cancer in experimental models in which mucosal destruction is chemically induced, with consequently profound alterations in the exposure of the immune system to intestinal bacteria. These findings further support the important role of innate receptors in cell-to-cell interactions, as well as in homeostatic control of the symbiotic relationship with the commensal flora, with apparently paradoxical effects on tumor initiation and progression.
The experimental studies and the clinical data on the role of MyD88 in cancer provide strong evidence that innate inflammation and innate immune receptors play a role in carcinogenesis. However, these findings also open many new questions regarding which cell signaling pathway is most important, which cells are involved in the production of ligands for MyD88-coupled receptors, and whether the TLRs or the IL-1-family receptors play the predominant role. Another key question is whether MyD88 signaling drives carcinogenesis by the induction of an inflammatory environment, or whether it directly affects the survival and proliferation of tumor cells.
While these overlapping molecular pathways provide experimental evidence for the role of innate inflammatory responses in carcinogenesis, the strongest clinical evidence in humans comes from the association between chronic infections and cancer, and the finding that regular aspirin or other NSAID therapy decreases the incidence of cancer.
NSAIDs function by inhibiting the cyclooxygenases (COXs), COX-1 and COX-2, which are responsible for the production of prostaglandins from fatty acids. These enzymes catalyze the synthesis of prostaglandin E2, which promotes inflammation by dilating blood vessels, allowing immune cells to pass from the blood into the tissues. This same signaling molecule also regulates angiogenesis and enhances hematopoietic cell homing, sending progenitor cells to damaged tissue to differentiate into the many immune cell types needed for repair. The constitutively expressed COX-1 contributes to the homeostasis of the gastrointestinal mucosa, whereas the inducible COX-2 is regulated by various pro-inflammatory cytokines. NSAIDs like aspirin inhibit both COX-1 and COX-2, explaining the considerable toxicity and damage to stomach and intestinal lining that can occur with these drugs. Selective COX-2 inhibitors, such as Vioxx, only inhibit the inducible COX-2 enzyme, which is activated during inflammation, leaving the gastrointestinal homeostasis untouched. Many of these drugs were, however, pulled from the market because of reported cardiovascular toxicity due to the shunting of the COX-2 substrate—arachidonic acid—into the 5-lipooxygenase pathway generating leukotrienes rather than prostaglandins.
Although initially identified as upregulated in colorectal cancer, COX-2 was found to be highly expressed in almost every type of tumor at the early stages of tumor formation. Indeed, COX-2–specific inhibitors increased both overall and recurrence-free survival following surgical resection, but only in the subset of colorectal cancer patients who overexpressed COX-2 or had mutated forms of the gene. Interestingly, not only did COX-2 inhibitors prevent cancer formation, but they also decreased the number of already established polyps in patients with familial adenomatous polyposis—an inherited disorder characterized by the early onset of colon cancer.12
Though such results are encouraging, both nonspecific COX inhibitors, such as aspirin, and COX-2–specific inhibitors have significant toxicity that needs to be balanced with their demonstrated benefits.12 The interesting point raised by Rothwell and colleagues in their meta-analysis is that the cancer-preventive effect of long-term daily treatment with NSAIDs is not limited to prevention of colon cancer in individuals with elevated risk due to reoccurring polyps or genetic predisposition. It is also effective for the prevention of sporadic colon cancer and many other gastrointestinal and nongastrointestinal solid tumors, including esophageal, pancreatic, stomach, lung, brain, and prostate cancers. Although the published analysis encompassed a very large number of individuals, the study had some limitations. For instance, the trials did not originally have cancer as an end point; the information available in the different trials was not always of the same precision; and the data for nongastrointestinal cancers (with the exception of lung cancer) did not reach full statistical significance despite the large number of patients analyzed. These data clearly provide a compelling case, however, for further assessment of whether targeting inflammatory pathways will result in cancer prevention.
Although COX inhibitors clearly have important anti-inflammatory activity, their preventive effect on cancer may also be due to other effects of these drugs, or to noninflammation-related effects of prostaglandins on vasodilation, angiogenesis, DNA mutation rate, epithelial-cell adhesion, or apoptosis. Yet the Rothwell team’s impressive clinical results, taken together with the extensive clinical and experimental evidence for a causative link between inflammation and cancer, raise the possibility that finely targeted studies of innate inflammatory pathways could lead to even more effective cancer prevention with fewer toxic side effects.
It is important to remember, however, that innate inflammation plays very important roles in normal tissue homeostasis, resistance to infections, and response to tissue damage, and that the same inflammatory pathways that are hijacked by tumors to promote their own progression also play important physiological roles in health. Obtaining a tumor-preventive effect by targeting these molecular pathways without negatively affecting the other physiological roles of these molecules may be a difficult task, one that will require a much deeper understanding of all the inflammatory molecular mechanisms involved in physiology, host defense, and carcinogenesis. Yet these are exciting times. Both the clinical evidence and the preclinical research raise the concrete possibility of a successful effort to prevent cancer by targeting inflammation, and this prospect should encourage strong support for further scientific efforts in this field of indisputable medical potential.
F1000 Member References:
|This article is adapted from an upcoming review in F1000 Medicine Reports. It will be available for citation at f1000.com/reports
April 6, 2011
April 8, 2011