Innate inflammation receptors, proinflammatory soluble factors, and inflammation-induced transcription factors have been identified that provide an understanding of some of the molecular pathways underlying the link between inflammation and cancer. However, the important role of the innate inflammatory pathways in host defense against pathogens and tissue damage as well as the maintenance of tissue integrity and homeostasis means that additional careful studies will be needed to identify anti-inflammatory interventions with the beneficial effect of tumor prevention without unacceptable toxic 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. Unfortunately, aspirin and other nonsteroidal anti-inflammatory drugs NSAIDs are not without problematic side effects, increasing the risks of liver toxicity and bleeding in the stomach and brain when taken over extended periods of time.
Researchers who have been studying the molecular pathways at the intersection of cancer and inflammation hope their findings may lead to more selective ways of reducing inflammation, eliminating or minimizing aspirin's negative effects without sacrificing its benefits. Recently, Rothwell et al. Many studies had previously shown that daily use of aspirin and other NSAIDs for extended periods reduced the risk of colorectal cancer or polyp recurrence, but no formal evidence in humans was yet available demonstrating that aspirin might also reduce risk in other cancers.
Rothwell et al. In trials in which the participants took aspirin for more than 7. For lung and esophageal cancer, the benefit was confined to 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 considered 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, years ago. Later the name was extended to include all malignant and infiltrating growths. In Rudolf Virchow noted white blood cells or leukocytes in neoplastic tissues and made a connection between inflammation and cancer. In many cases, one can see a direct connection between the inflammation caused by infectious pathogens and cancer.
Some pathogens can directly induce cell transformation but most, if not all, also induce a state of chronic inflammation that favors initiation and progression of tumors. Because new pathogens associated with or causing cancer are continuously being identified, it is likely that these frequencies are underestimates.
In addition to pathogens, several states of noninfectious chronic inflammation triggered by mechanical, radiation, chemical, or genetic factors have been associated with human malignancy.
However, even in the absence of specific infections by pathogens, the interaction of the organism with commensal microbes is likely to help establish inflammatory conditions favoring carcinogenesis either in epithelia exposed to the outside environment or affected systemically. The increased risk of colorectal carcinoma in patients with ulcerative colitis or Crohn's disease stems from colorectal inflammation caused by the patients' immune systems reacting to intestinal commensal flora. But a systemic inflammatory response to commensal microbes can also occur when bacterial transmucosal translocation takes place because of immunodeficiency or epithelia damage.
In these cases, the systemic inflammatory response is directly induced by bacteria and bacterial products or by the systemic diffusion of proinflammatory molecules such as cytokines and chemokines in the bloodstream. This phenomenon can be seen in the increased prevalence of tumors at sites other than the gastrointestinal tract in human colitis patients [ 2 ] and the state of chronic inflammation and immune activation in HIV-infected patients with altered mucosal permeability [ 3 ].
Chronic inflammation can promote all phases of carcinogenesis, from favoring the initial genetic alterations that give rise to tumor cells, to acting as a tumor promoter by establishing an environment in the surrounding tissues that allows the tumor to progress and metastasize, to triggering immunosuppressive mechanisms that prevent an effective immune response against the tumors. Many molecular mechanisms of innate inflammation have several or all of these protumor effects.
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In the tissue in which cancer originates, infiltrating hematopoietic cells, epithelial cells, endothelial cells, fibroblasts, and other stromal cells are all responsible for the establishment of inflammation by secreting and responding to proinflammatory factors such as cytokines, chemokines, growth factors, and proteases. This proinflammatory environment attracts more infiltrating inflammatory cells and regulates tissue rearrangement, angiogenesis, and the ability of transformed cells to grow and to migrate.
The tumor cells also participate in these processes by activating mechanisms of intrinsic inflammation in the surrounding epithelial or stromal cells, which often show genetic and epigenetic oncogenic alterations similar to those in the tumor cells. These genes turn on the inflammatory pathway within the cell and activate inflammation outside the cell by recruiting and activating inflammatory cells, creating an environment that reduces anticancer immune cell defenses [ 6 ]. Interestingly, by way of epigenetic changes, continued activation or overexpression of oncogenes may not always be required for maintaining this proinflammatory loop: transient activation of the SRC oncoprotein induces an epigenetic switch that uses microRNA regulation to stably maintain the production of interleukin IL -6, a key inflammatory cytokine [ 7 ].
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 proinflammatory 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 [ 8 ] through a positive feedback loop. Thus, the intrinsic inflammatory response in transformed or damaged tissue cells is an innate inflammatory response to genetic and other insults that may well represent a host response mechanism that is not yet fully understood but is likely to play an important role not only in carcinogenesis but also in the response to alterations of tissue homeostasis or pathogen-induced damages, and in the pathogenic mechanisms of chronic inflammatory diseases.
In recent years, researchers have begun to appreciate the role that a tumor's environment plays in its growth and survival. Indeed, inflammation of the tissue surrounding a tumor can hasten the oncogenic process by directly promoting genetic instability and favoring or inducing gene mutations.
Reactive oxygen and nitrogen species ROS and RNS , which are abundant during inflammation, can induce DNA mutations, epigenetic alterations, and post-translational modifications of proteins that control the cell cycle or survival [ 9 ]. Interestingly, the direct interaction of mucosal epithelial cells with oncogenic pathogens such as H. Aberrant expression of activation-induced cytidine deaminase, an initiator of somatic hypermutation during B-cell maturation, was abnormally activated in inflamed epithelial cells—an effect linked to mutations seen in human colorectal cancer [ 11 ].
These mechanisms suggest that genomic instability, epigenetic changes, and functional protein modifications are involved in the early events of inflammation-induced cancer initiation. Signal transducer and activator of transcription 3 STAT3 is another major transcription factor involved in immunity and inflammation. In this respect, it is clear that a subtle balance of low and high PRR activity is required for proper functioning of the immune system. On the other hand, if downstream members of PRR pathways are underexpressed, inactivated, or unable to work properly, it may result in the same effects that of diminished PRR activity, and therefore a balance in functioning of all genes encoding proteins constituting PRR signaling pathways should be preserved for optimal immune system function 7 , 8.
Three years ago, four milestone reviews on PRR biology were published in Immunity 9 — 12 ; we now think that Frontiers in Immunology can be an excellent platform for the constellation of review articles systematizing key information in the field with regard to the recent discoveries. With this aim in mind, we invited a number of recognized experts in the field to submit review papers on various aspects of PRR biology and their role in cancer.
We sincerely thank all researchers who have agreed to contribute to our Research Topic. This collection is divided into three sections.
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We also sought to solicit a number of additional review articles on TLR and NLR biology, since we believe these topics deserve a particular attention. In addition, a brilliant review by Nelson Di Paolo fills a substantial gap in the understanding of the recognition of human oncogenic viruses by PRRs.
The second section is devoted to the role of PRRs in various vital cellular processes, including apoptosis, DNA repair, autophagy, and angiogenesis. Finally, the last piece of the collection consists of reviews that comprehensively analyze the impact of PRRs on the development of malignant tumors esophageal cancer, gastric cancer, colorectal cancer, lung cancer, prostate cancer, breast cancer, ovarian cancer, and lymphoma.
Furthermore, Simon Heidegger and colleagues discuss the role of PRRs in graft-versus-host disease and graft-versus-leukemia following allogeneic stem cell transplantation.
Genomics of Pattern Recognition Receptors : Applications in Oncology and Cardiovascular Diseases
As a final point, Shanjana Awasthi underlines the importance of TLR agonists in cancer immunotherapy. We created this Research Topic with the hope that it will be useful for a wide audience, particularly cancer researchers, immunologists, microbiologists, graduate, and undergraduate students of biomedical faculties as well as for their lecturers. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Published online Sep Anton G. Yuzhalin 2. Arseniy E. Author information Article notes Copyright and License information Disclaimer. Kutikhin, moc. Specialty section: This article was submitted to Tumor Immunity, a section of the journal Frontiers in Immunology. Received Aug 2; Accepted Sep 4. Monaco Group Cardiovascular Inflammation. Our team. Jennifer Cole Research Associate. Inhye Park Postdoctoral Assistant. David Ahern Research Associate. Natacha Zanin Postdoctoral Researcher. Michael Goddard Senior Technician. Warren Baker Laboratory Research Technician.
Laura Collins DPhil Student.