Inflammatory cells found within tumors and surrounding tissue include lymphocytes, macrophages and dendritic cells. Tumor associated macrophages have multiple actions that may contribute to carcinogenesis. Macrophages have been shown to generate nitric oxide, induce angiogenesis, and produce cytokines. Among the cytokines commonly produced by macrophages are the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β).
TNF-α is a major inflammation mediator involved in tissue destruction and remodeling. TNF-α may induce cellular proliferation or apoptosis depending, in part, on the concentration of TNF-α. High concentrations of TNF-α have been shown to have anti-cancer actions by targeting tumor vasculature whereas chronic exposure to low levels of TNF-α may act as a tumor promoter. Evidence of TNF-α-induced cell survival signaling has been demonstrated using mouse models. In mice, homozygous deletion of the TNF-α gene attenuated chemically-induced skin carcinogenesis. Moreover, recent studies suggest that TNF-α may induce ROS production and identified TNF-α as an endogenous mutagen. Thus, inflammation and, more specifically, TNF-α has become a focus of several studies investigating the role of inflammatory cytokines on oncogenic transformation.
The importance of TNF-α in inflammation based cancers is due, in part, to the activation of NF-κB. NF-κB mediates a number of oncogenic events including proliferation, invasion, and angiogenesis. In hepatocellular cancer, suppression of NF-κB activation using an anti-TNF-α neutralizing antibody induced apoptosis in malignant cells.
IL-1β is a secreted 17 kDa proinflammatory cytokine formed from the cleavage of the IL-1 gene product by Interleukin-1β Converting Enzyme (ICE, caspase 1). High levels of IL-1β are found in the tumor microenvironment and may be important in the procarcinogenic role of local inflammation. In IL-1β gene targeted mice, chemical induced tumor incidence was reduced compared to wild type and Il-1α (-/-) mice. Moreover, IL-1β was shown to be required for tumor invasiveness and angiogenesis and may enhance its own oncogenic properties by inducing the ex
Over the last two decades about 50 human chemokines have been identified as a family of functionally related small secreted molecules with leukocyte chemoattractant and cytokine-like activities. Chemokines exert their biological activities by interacting with a distinct subfamily in the rhodopsin-like seven transmembrane G-Protein coupled receptor (GPCR) super family. At this time, 18 chemokine receptors have been molecularly defined, 10 for CC chemokines (CCR1 to 10), 6 for CXC chemokines (CXCR1 to 6), and 1 for C chemokines and CX3C chemokines (XCR1 and CX3CR1, respectively). Chemotaxis induced by chemokines plays a crucial role in leukocyte migration, both during resting conditions for control of leukocyte homeostasis (constitutive chemokines) as well as under conditions of infection and/or inflammation induced by proinflammatory mediators (inflammatory chemokines).
The seven transmembrane chemokine receptor D6 binds specifically to inflammatory CC-chemokines without transducing any intracellular signals necessary for chemo attraction. The D6 receptor internalizes its pro inflammatory ligands through a β-arrestin dependent pathway, targets them to degradation and thus clears inflammatory response. The role of D6 in scavenging inflammatory chemokines is evident from different animal models using D6 null mice. The D6 deficient mice had accumulated higher amount of inflammatory chemokines in skin compared to wild type mice after phorbal ester application. The human D6 receptor is normally expressed on lymphatic endothelial cells within the skin, gut and lung tissues. Later, it was shown by quantitative real time polymerase chain reaction (qPCR ) analysis of human and murine leukocytes, D6 ex