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=Inflammation and Cancer=

Introduction
When functioning properly, the immune system serves to protect individuals from foreign invaders (bacteria and viruses), detect cells with mutations (DNA damage), and activate a wound healing response. It is the latter function of the immune system that has been shown to be involved with the development and promotion of many types of cancers. During a wound healing response, inflammation occurs because immune cells accumulate at the site of tissue damage. The immune cells try to repair the damaged tissue by releasing various chemical signals (cytokines/chemokines) to create an environment that promotes cellular proliferation (growth). The immune cells maintain this enriched environment until the damaged tissue has been repaired or replaced with healthy tissue. When the body is unable to heal itself, chronic inflammation results and the enriched environment for cell proliferation is maintained for long periods of time. These circumstances create a favorable environment in which cells having undergone mutations can proliferate and lead to the development of cancer. Certain types of cancers can even release their own cytokines/chemokines to potentiate the state of chronic inflammation in order to further their own growth and development. As a result, cancer is sometimes referred to as wounds that never heal. The table below (Table 1) lists a variety of chronic inflammatory conditions that have been found to predispose individuals to different types of cancers.

Acute Inflammation
Acute inflammation normally results from a minor injury and consists of an ordered structure of events that lead to wound healing (Figure 1a). During an acute inflammatory response and the subsequent repair that prevails, resident immune cells (e.g. mast cells, macrophages, and dendritic cells) located near the site of injury become activated and recruit other immune cells including granulocytes, additional macrophages, and T-helper cells to the inflamed site of injury or infection. Mesenchymal cells (e.g. fibroblasts and endothelial cells) are also recruited to the site of injury and activated to promote healing by initiating the formation of new blood vessels and extracellular matrix. These immune cells promote the maintenance and regeneration of tissue by releasing pro-inflammatory cytokines/chemokines that create an enriched environment for cell growth, angiogenisis, and tissue remodeling. Once the wounded tissue has been repaired, the pro-inflammatory signals are ablated and anti-inflammatory signals are released in order to return the microenvironment to homeostasis. FIGURE 1: Wound healing response (a) versus invasive tumor growth (b) 

Chronic Inflammation
Chronic inflammation results when the body is unable to reconcile futile attempts to heal itself, yet it continues to try. These circumstances create a favorable environment in which cells having undergone mutations can proliferate and lead to the development of cancer. Research has found that a variety of chronic inflammatory conditions predispose organisms to the initiation and promotion of cancer (as shown in Table 1).

Chronic Inflammation and Tumor Initiation
There are several theories as to how chronic inflammation can lead to cancer. One of which being that cancers arise as a result of both infection and inflammation. The logic behind this theory is that the virus that causes the chronic inflammation condition also transforms cells in the inflamed environment with oncogenes. The inflamed environment that is created by the cytokines and chemokines released from the immune cells creates an environment that increases cell proliferation, including those cells that have been transformed with oncogenes. The human papillomavirus is an example of one type of virus that is thought to initiate the development of cancer in this way. In addition, chronic inflammation is also thought to initiate cancer development by the leukocytes and other phagocytic cells located in the inflamed environment and release reactive oxygen and nitrogen products that induce DNA damage. These reactive products include reactive oxygen intermediates (ROI), hydroxyl radical (OH·), superoxide (O2-·), reactive nitrogen intermediates (RNI), and nitric oxide (NO·). These reactive products, combined with the enriched environment for cell proliferation, allow DNA mutations to accumulate within cells and cause them to become neoplastic.

Chronic Inflammation and Tumor Promotion
The expansion of a tumor mass is potentiated by precise orchestration of neoplastic events within the tumor microenvironment, which include increased cellular proliferation, the development of angiogenic vasculature, and tissue remodeling(Figure 1b). Neoplastic cells further their growth not only by recruiting inflammatory cells to the microenvironment to promote secretion of proinflammatory cytokines/chemokines, but they also have the ability to regulate the production of their own proinflammatory chemical signals (Figure 2). Neoplastic cells also shift the cytokine/chemokine balance toward pro-angiogenic factors in order to increase the formation of neovasculature, thus enabling transformed cells to control their own blood supply. This shift toward pro-angiogenic factors is seen not only in cancer, but can also be observed in other forms of chronic inflammatory diseases including psoriasis, rheumatoid arthritis, and fibrosis. Formation of invasive cancerous fronts and the remodeling of extracellular matrix are what promote neoplasms to metastasize to other organs and tissues. There is still ongoing debate surrounding whether malignant populations of cells migrate to an environment that is favorable to further growth and development or that specific organs or tissues attract malignancies through an unknown mechanism involving chemotaxis.

FIGURE 2: Interactions between tumor and immune cells via secreted cytokines 

Cells Involved
T cells T regulatory cells, also known as Treg cells, are involved in the induction and maintenance of the peripheral immune system. TReg cells exert their immunosuppressive affects by tempering the immune system's ability to recognize between self and non-self antigens in efforts to uphold homeostatic immunity. However, in the context of cancer, tumors are thought to suppress induction of tumor-associated antigen (TAA)-specific immune cells through a mechanism of trafficking, differentiation, and expansion of TReg cells in the tumor microenvironment. Because TReg cells are thought to suppress the activity of TAA-associated T cells, tumors may evade anti-tumor immunity in this way. Phagocytes Recent studies have indicated that macrophages promote tumor growth and metastasis. Macrophages are recruited to the tumor microenvironment by CSF-1 and VEGF. Macrophages that have been recruited to the tumor microenvironment are referred to as tumor-associated macrophages (TAMs). Studies have shown that solid tumors have high concentrations of TAMs and that having a high density of TAMs is correlated with poor prognosis. One way in which TAMs promote tumorigenesis is by increasing the secretion of important cytokines involved in angiogenesis including vascular endothelial growth factor (VEGF), interleukin IL-1, IL-8, tumor necrosis factor-α (TNF-α), matrix metalloproteinases MMP-9, MMP-2, and nitric oxide (NO). In addition to increasing angiogenic cytokines, TAMs can also promote tumor growth by producing various growth factors. These cytokines include fibroblast growth factor (FGF), colony-stimulating factor (CSF-1), hepatocyte growth factor (HGF), epidermal-growth-factor receptor (EGFR)-family ligands, platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β). Dendritic cells are derived from monocytes that have differentiated in the presence of various pro-inflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-4, and TNF. Dendritic cells first exist in an immature form until they are activated and differentiate into a mature form. Immature dendritic cells are recruited to the site of inflammation where they then capture antigens, undergo maturation, and migrate to secondary lymphoid organs. Upon reaching the lymph nodes, dendritic cells present their antigens to various immune cells including naive CD4+ and CD8+ T cells, naive and memory B cells, and natural killer cells. Dendritic cells located in tumor environments are often found in immature form and are unable to activate T-cells. In addition, research has also shown that dendritic cells located in tumor environments are often able to present exogenously acquired antigens on MHC I molecules rather than on MHC II molecules, which further helps tumor cells evade recognition by the immune system. Mast cells Mast cells arise from hematopoietic progenitor cells and reside within nearly all vascularized tissues in positions near blood vessels, nerves, smooth muscle cells, and epithelial cells. Upon activation, mast cells release a wide variety of biologically active molecules contained within their cytoplasmic granules. Mast cell products elicited upon degranulation include such things as MCP-4 (chymase) which has been shown to activate progelatinase B and induce angiogenesis within hyperplastic skin and MCP-6 (tryptase) which has been shown to have mitogenic activity within dermal fibroblasts. A recent study has shown that mast cell deficiency in HPV16 transgenic mice lead to a model of biphasic control in which hyperplastic and dysplastic stages of tumorigenesis mast cells activate dermal fibroblastic proliferation. Directly and through progelatinase B activation angiogenic activators are turned on by mast cells until in the latter phase of biphasic control where tumor cells have the ability to control the development of their own blood supply. TABLE 2: Immune Cells Involved in Cancer Defense 
 * Regulatory T Cells
 * NKT
 * macrophages
 * Dendritic Cells
 * Granulocytes
 * Neutrophils

Cytokines/Growth Factors
TNF-α Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine whose action on developing tumors is context dependent. Administration of TNF- α at high levels is thought to function in tumor necrosis due to its ability to destroy tumor vasculature via endothelial cell apoptosis. Chronically low levels of endogenous TNF-α however, have been shown to be an important contributor of early tumor development. Release of TNF-α from cancer and stromal cells enables activation of reactive oxygen intermediates, inflammatory enzymes, matrix metalloproteinases (MMPs), cell adhesion molecules, and other cytokines. Main sources of TNF-α include macrophages. Overexpression of TNF-α has been shown to be present within the following malignancies: breast, ovarian, colorectal, prostate, bladder, oesophageal, renal cell cancer, melanoma, and lymphomas and leukaemias. Recent studies have also shown that TNF-α-deficient mice developed a fraction of the epithelial tumors attained by wild type counterparts upon exposure to carcinogenesis.

TGF-β TGF-β is an immunosuppressive cytokine which inhibits T cell proliferation, the immune functions of antigen-presenting cells (APCs), and prevents the differentiation of nascent T cells into cytotoxic T cells or effector T cells. Its production is associated with T cells, natural killer (NK) cells, macrophages, cancerous cells, epithelial cells, and stromal cells. In a study performed by Bhowmick and colleagues, results from conditional inactivation of the TGF-β type II receptor in fibroblasts support the notion that absence of TGF-β signaling leads to the development of cancer. However, other studies have supported a role for TGF-β as an inhibitor of the anti-tumor immune response upon T-cell specific ablation of TGF-β. Unsure how to reconcile its involvement in stimulation of epithelial growth and promotion of tissue regeneration.

IL-12/IL-23 Interleukins-12 and interleukin-23 are both members of the small family of pro-inflammatory heterodimeric cytokines. They share a common p40 subunit and covalently link either to a p35 subunit to form IL-12 or to a p19 subunit to form IL-23. While prevalent sources of IL-12 and IL-23 include dendritic cells and phagocytic cells, these particular interleukins lead differing immunological pathways. IL-12 directs the development of naive T cells into T-helper 1 (Th1) cells and fosters increased levels of cytotoxic T cells. IL-23 has been shown to upregulate MMP9, increase the level of angiogenesis, and decrease the infiltration of CD8+ T cell populations within the tumor microenvironment. By inducing expression of both IL-17 and G-CSF, cytokines linked to the development of tumors, IL-23 has the ability to modulate neutrophil infiltrate.

CSF-1 The macrophage colony-stimulating factor (CSF-1) is a growth factor that promotes the proliferation, differentiation, and survival of macrophages and other mononuclear phagocytes. In addition to being a growth factor, CSF-1 also serves as a chemoattractant for mononuclear phagocytic cells and can cause hematopoietic stem cells to differentiate into macrophages or other related cell types. CSF-1 is secreted by macrophages and is overexpressed in various tumors of the reproductive system including ovarian, breast, and prostate cancers. Studies have shown that the overexpression of CSF-1 results in increased leukocytic infiltration and poor prognosis. On the contrary, the ablation of CSF-1 has been shown to significantly reduce tumor progression to malignancy and metastasis. The results from this study suggest that CSF-1 enhances tumor development by recruiting tumor-associated macrophages to the microenvironment, which then promote angiogenesis, matrix degradation, and cellular proliferation.

TABLE 3: Cytokines Involved in Cancer Inflammation  

Signaling Molecules
NF-κB Nuclear factor-κappa B (NF-κB) is a transcription factor that regulates genes whose products stimulate cellular proliferation, suppress evasion from programmed cell death (apoptosis), promote the epithelial-to-mesenchymal transition, in addition to involvement with inflammation and immunity. NF-κB is present within nearly all cell types and its activation occurs through stimulation by a variety of proinflammatory cytokines. It has known actions as a tumor promoter in the later developmental stages of cancer resultant from inflammation.

SMAD4 SMADs are a family of transcription factors that mediate TGF-β signaling, which is an important regulator of T-cell activation, differentiation, and cytokine production. SMAD mutations and alterations of its expression have been identified in various types of human cancers. The alteration of SMAD4, which is one type of SMAD protein, has been linked to several types of cancer including gastrointestinal, prostatic , and pancreatic cancers. Research has shown that SMAD4 is an essential signaling mediator for T-cell differentiation and that the absence of SMAD4 in T cells results in spontaneous epithelial cancers in the murine gastrointestinal tract.

Tumor Immunoediting
Although tumors often develop the ability to manipulate the inflammatory response to potentiate their own growth, there are circumstances in which the immune system is able to detect the cancerous cells and restrict their growth. When malignant pathogenesis does occur within an organism, it may be said that the immune system has in part failed to rid the organism of foreign invaders, whether by mechanisms of immune tolerance or immune system evasion. However, all is not necessarily lost. There are circumstances in which the immune system is able to recognize the tumor cells and restrict their growth. Part of keeping a malignant population of tumor cells in check is that the immune system maintain that these foreign invaders be recognized as aberrant cells. Such a process is called tumor immunoediting (see Cancer Immunology), and works to keep tumor cells under strict growth control so they are unable to metastasize to other organs or tissues by evolving mechanisms in which to evade immunity.