An association between inflammation and cancer was noted more than a century ago by the Rudolph Virchow, based on the presence of leukocytes in neoplastic tissue. This hypothesis has been supported by more recent epidemiological data which estimated that approximately 20% of cancer deaths are related to persistent inflammation and chronic infections (Karin M 2008). Cancer-related inflammation is the seventh hallmark of cancer. Some of the major examples of inflammation related cancers are cervical cancer (Human papilloma viruses), gastric cancer (Helicobacter pylori), liver cancer (Hepatitis B virus), nasopharyngeal carcinomas (Epstein-Barr virus), Kaposi's sarcoma (Kaposi's sarcoma herpesvirus) and T-cell luekemia (Human T-cell luekemia virus) and colitis-associated cancer (CAC).
Inflammation is a physiological process vital for the function of the innate immune system due to its response to acute tissue damage, whether that is resulting from physical injury, infection, exposure to toxins, ischemic injury, or other types of trauma. Immune cells can regulate almost every stage of cancer development. Inflammation may become chronic either due to dysregulation in the control mechanisms that normally turn the process off or persistent of inflammatory stimulus. Recently, it has been suggested that inflammation was associated with cancer is similar to that seen with chronic inflammation, which induces gene mutations, inhibiting apoptosis, or stimulating angiogenesis and cell proliferation (Kundu and Surh 2008). Many cancers arise from sites of infection, chronic irritation, and inflammation; which clarify that the tumour microenvironment is largely arranged by inflammatory cells.
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Almost about one-sixth of all cancer cases are contributed by the chronic inflammation and infection. Free radicals (O2-, OH- and NO-) growth factors, prostaglandins and cytokines are mediators of the inflammatory response which can induce epi-genetic and genetic changes in tissue, including point mutations in tumor suppressor genes, post-translational modifications and DNA methylation; causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer (Hussain and Harris 2007). In fact, chemokines and cytokines play an important role in the adaptive immunity, angiogenesis and metastasis. Cytokines regulate immunity, haematopoiesis and inflammation; and examples are interleukins (ILs), growth factors, interferons (IFNs) and tumor necrosis factors (TNFs). They are characteristically categorised into two groups; pro-inflammatory (e.g. IL-1, IL-6, IL-8, TNFÎ±, IFN-g) and anti-inflammatory (e.g. IL-4, IL-10, TGF-Î² and vascular endothelial growth factor (VEGF) which binds to receptors and transducer signals via second messengers to control growth, differentiation and activation of cells. Chemokines are soluble chemotactic cytokines, which are classified as four major groups, i.e., CXC, CC, XC and CX3C primarily based on the positions of conserved cysteine residues in chronic inflammation and recruiting leukocytes at the site of inflammation is the central role of chemokines (Kundu and Surh 2008).
Although IL-6 is generally viewed as a pro-inflammatory cytokine but it is a pleiotropic cytokine which is a major mediator of inflammation and activator of signal transducer and activator of transcription 3, serves to block apoptosis in cells during the inflammatory process, keeping them alive in very toxic environments. The ability of IL-6 to directly activate the signal transducers and activators of transcription (STAT) factors STAT1 and STAT3, via the Janus kinases (JAK) produces serious unintended consequences when examined in the context of progression to neoplasia (Hodge et al 2005).
Reactive oxygen species (ROS) becomes the primary mediators of free radical reactions in cells, which are generated during the production of ATP by aerobic metabolism in mitochondria. The leakage of electrons from mitochondria, during the electron-transport steps of ATP production, generates ROS. It is a group of highly reactive molecules, which can react quickly and damage various types of biomolecules, including proteins, DNA and lipids. The balance of ROS formation and anti-oxidative defense level is crucial for cell survival and growth, and it is very important for the cell to remove ROS properly for it to remain viable and maintain its vital function. Anti-oxidative defense systems include intracellular superoxide dismutase (SOD), catalase and glutathione peroxidase that eliminate O2 and H2O2. Antioxidants may play a role in balancing the harmful effect of free radicals that leads to cancer. Oxidative stress occurs when free radical generation exceeds the system's ability to neutralize and eliminate them. It was thus suggested that inhibiting or scavenging ROS would lead to the therapeutic modality for ROS-related diseases; utilizing either anti-oxidative compounds or enzymes (Fang et al 2009).Continued oxidative stress can lead to chronic inflammation. Oxidative stress can activate a variety of transcription factors including nuclear factor (NF)-ÎºB, activator protein (AP)-1, p53, hypoxia-inducible factor (HIF)-1Î±, peroxisome proliferator-activated receptor (PPAR)-Î³, Î²-catenin, and NF-E2 related factor (Nrf)-2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules (Karin M 2008).
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Tumour-associated macrophages (TAMs) are a significant component of inflammatory infiltrates in neoplastic tissues and are derived from monocytes that are recruited largely by monocyte chemotactic protein (MCP) chemokines. TAMs have a dual role in neoplasms, although they may kill neoplastic cells following activation by IL-2, interferon and IL-12 and they produce a number of potent angiogenic and lymph-angiogenic growth factors, cytokines and proteases, all of which are mediators that potentiate neoplastic progression (Sica et al 2008). Further evidence for the role of inflammation has come from the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of spontaneous tumour formation in people with familial adenomatous polyposis (FAP). The ability of NSAIDs to inhibit cyclo-oxygenases (COX-1 and -2) underlies their mechanism of chemoprevention. COX-2 converts arachidonic acid to prostaglandins, which in turn induces inflammatory reactions in damaged tissues (Ulrich et al 2006).
Cancer-related inflammation has been recently described as "extrinsic" (driven by inflammatory conditions that increase the risk of cancer) or "intrinsic" (due for example to the activation of oncogenes that induce a transcriptional pattern similar to that which occurs during inflammation) (Mantovani et al 2008).
Inflammation may be a key element in the etiology of colorectal cancer (CRC). People with idiopathic inflammatory bowel disease (ulcerative colitis and Crohn's disease) have a greater likelihood of developing colon cancer. People who use NSAIDs like aspirin have consistently been shown to have lower risk of CRC than non users. There is little information on the association between inflammation-related factors and specific acquired epigenetic and genetic changes in rectal tumors. Some studies suggest that TP53 mutations may be induced by inflammation-related processes and other studies have implicated inflammation as a contributor to CpG Island Methylated (CIMP) tumors (Itzkowitz and Yio 2004). Study done by (Slattery et al 2009) suggested that inflammation-related factors including use of aspirin and NSAID, dietary carotenoids and antioxidants, and IL6 rs1800795 and rs1800796 polymorphisms are associated with specific rectal tumor mutations. Associations were more consistent and stronger for TP53 mutations than for either CIMP-positive or KRAS2 mutations shows TP53 is a target of inflammation in that a mutated TP53 gene is associated with increased inflammatory process while wild-type TP53 demonstrates less inflammatory processes.
Furthermore, it is now well recognized that chronic infection with Helicobacter pylori is tightly associated with the development of gastric cancer, primarily noncardiac gastric cancer. The infection with H pylori triggers an extensive systemic and local inflammatory response. Despite declining rates in the most developed countries, it remains a major public health problem in much of the world especially in parts of East Asia, South America and Eastern Europe and accounts for the second most common cause of the cancer related death worldwide. Over 90% of all gastric cancers are adenocarcinoma and the remaining 10% are largely lymphomas and leiomyosarcomas. According to the Lauren classification, histologically; adenocarcinoma of gastric are divided into two types: an intestinal type in which the neoplastic cell form glandular structures and a diffuse type where there is no cohesion between neoplastic cells, so that they infiltrate and thicken the stomach wall without forming a discrete mass. The oncogenes EGF, h-Ras, Erb-B3 are over-expressed in gastric cancer and loss of the tumour-suppressor genes MCC (mutated in colorectal cancer), APC (adenomatous polyposis coli) and p53 occur in 30-65% of tumours (Phan and Jaffer 2003).
H. pylori display a considerable amount of genetic variation. Even strains within an individual host commonly change over the course of the infection. The majority of H pylori strains express and secrete VacA, avacuolating cytotoxin, which is inserted into the gastric epithelial-cell and mitochondrial membranes, possibly providing the bacterium with nutrients and inducing apoptosis of the host cell. VacA has also been found to modulate the host immune system via T-cell inhibition. Studies indicate that expression of VacA increases bacterial fitness and in some western countries VacA s1 and VacA m1 genotypes are associated with more severe forms of gastritis, atrophy, intestinal metaplasia and perhaps gastric cancer (Crowe S E 2005).
Another major focus of research is the analysis of the cag pathogenicity island (cag PAI), a genomic fragment comprising 31 genes that support the translocation of the 120-kD CagA protein into the gastric epithelial cell. CagA has been shown to induce cytokine production along with a growth factor like response in the host cell and to disrupt the junction mediated gastric epithelial cell barrier function. In western countries, patients carrying CagA+ H pylori strains are more likely to develop adenocarcinomas of the distal stomach than patients infected with CagA- strains. In particular, one recent meta-analysis of case-control studies concluded that infection with CagA+ strains increases the risk over H pylori infection alone. Interestingly, the combination of pro-inflammatory polymorphisms in the interleukin-1Î² gene and infection with more virulent H pylori strains seems to increase the gastric cancer risk even more. Recent data by Goto et al (2006) also indicate that a common polymorphism in the coding gene for SHP-2 that interacts with the CagA protein can increase the risk for gastric atrophy in Japanese patients infected with CagA+ H pylori strains. The studies by Watanabe and Honda found that 37% and 40% of infected animals developed well-differentiated intestinal adenocarcinomas 62 and 72 wk after inoculation of the bacterium. Both studies used cagA and vacA positive H pylori strains for infection of the animals.
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The identification of transcription factors such as NF-ÎºB, AP-1 and STAT3 and their gene products such as interleukin-6, interleukin-1, chemokines, COX-2, tumour necrosis factor, VEGF, adhesion molecules and others have provided the molecular basis for the role of inflammation in cancer. The role of ROS in various phases of tumorigenesis is therefore, targeting redox-sensitive pathways and transcription factors offers great promise for cancer prevention and therapy. Others condition associated with chronic irritation and subsequent inflammation predispose to cancer are long-term exposure to cigarette smoke, asbestos, and silica. The association between inflammation and cancer was further strengthened by recent discovery of an interaction between microRNAs and innate immunity during inflammation.