Normal epithelium Chronic inflammation Inflammatory mediators Cytokines/growth f
ID: 3477391 • Letter: N
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Normal epithelium Chronic inflammation Inflammatory mediators Cytokines/growth factors Keratinocytes (KC) High/stable B7-H1 Signalings for 87-H1 induction MEKUMAPK/ERK PI3K/AKT/mTOR JAK/STATs,IRF-1 Basement membrañe No B7-H1 expression EMT Snail family E-cadherin . Cancerous cell change Cell cycle/proliferation PTEN, cyclin Apoptosis/survival Ki67, Bcl-2 Adhesion/migration Malignant conversion B Transient inflammation Tumor progression KC expansion chemokine/ cytokine secretion Immune escape Tumor-associated B7-H1 87-H1 induction Lymphocytes Cytokines IFN-Y, IL-1 Effector T/NK cells Regulatory T cells Cellular malignancy? Tunor invasion metastasis Neutrophils Regulation of inflammation Inflammatory cells O 2011 American Association for Cancer Research Cancer Research Reviews AMRExplanation / Answer
Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. They are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically or antagonistically. Cytokines are made by many cell populations, but the predominant producers are helper T cells (Th) and macrophages. Cytokines may be produced in and by peripheral nerve tissue during physiological and pathological processes by resident and recruited macrophages, mast cells, endothelial cells, and Schwann cells. Following a peripheral nerve injury, macrophages and Schwann cells that gather around the injured site of the nerve secrete cytokines and specific growth factors required for nerve regeneration.
Cytokine network. Several different cell types coordinate their efforts as part of the immune system, including B cells, T cells, macrophages, mast cells, neutrophils, basophils and eosinophils. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted cytokines. Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types. T cells secrete a variety of factors to coordinate and stimulate immune responses to specific antigen, such as the role of helper T cells in B cell activation in response to antigen. The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well. Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. There is abundant evidence that certain pro-inflammatory cytokines such as IL-1, IL-6, and TNF- are involved in the process of pathological pain. A variety of cytokines are known to induce chemotaxis. One particular subgroup of structurally related cytokines is known as chemokines. The term chemotactic cytokines (CHEMOtactic CytoKINES) usually refers to this. These factors represent a family of low molecular weight secreted proteins that primarily function in the activation and migration of leukocytes although some of them also possess a variety of other functions. Chemokines have conserved cysteine residues that allow them to be assigned to four groups: C-C chemokines (RANTES, monocyte chemoattractant protein or MCP-1, monocyte inflammatory protein or MIP-1, and MIP-1), C-X-C chemokines (IL-8 also called growth related oncogene or GRO/KC), C chemokines (lymphotactin), and CXXXC chemokines (fractalkine).
The anti-inflammatory cytokines are a series of immunoregulatory molecules that control the pro-inflammatory cytokine response. Cytokines act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response. Their physiologic role in inflammation and pathologic role in systemic inflammatory states are increasingly recognized. Major anti-inflammatory cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. Leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF)- are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances. Specific cytokine receptors for IL-1, TNF-, and IL-18 also function as inhibitors for pro-inflammatory cytokines. Among all the anti-inflammatory cytokines, IL-10 is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-, IL-6 and IL-1 by activated macrophages.
Instructed cell migration is a fundamental component of various biological systems and is critical to the pathogenesis of many diseases including cancer. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. However, functional mechanisms of chemokine are not well implicit, which is crucial for designing new therapeutics to control tumor growth and metastasis. Multiple functions and mode of actions have been advocated for chemokines and their receptors in the progression of primary and secondary tumors. In this review, we have discussed current advances in understanding the role of the chemokines and their corresponding receptor in tumor progression and metastasis.
Chemokines, their receptors, and predominant receptor repertoires in different leukocyte populations are listed. The selected ligands are identified with one old acronym and the new nomenclature, the first part of the name identifies the family and L stands for “ligand,” followed by a progressive number. Chemokine acronyms are as follows: BCA, B-cell activating chemokine; BRAK, breast and kidney chemokine; CTACK, cutaneous T-cell–attracting chemokine; ELC, Epstein-Barr virus–induced receptor ligand chemokine; ENA-78, epithelial cell–derived neutrophil-activating factor (78 amino acids); GCP, granulocyte chemo attractant protein; GRO, growth-related oncogene; HCC, hemofiltrate CC chemokine; IP, interferon-inducible protein; I-TAC, interferon-inducible T-cell A chemo attractant; MCP, monocyte chemo attractant protein; MDC, macrophage-derived chemokine; Mig, monokine induced by interferon; MIP, macrophage inflammatory protein; MPIF, myeloid progenitor inhibitory factor; NAP, neutrophil-activating protein; PARC, pulmonary and activation-regulated chemokine; RANTES, regulated upon activation normal T cell–expressed and secreted; SCM, single C motif; SDF, stromal cell–derived factor; SLC, secondary lymphoid tissue chemokine; TARC, thymus and activation-related chemokine; TECK, thymus-expressed chemokine. Ba, basophils; CC, chemokine with the first 2 cysteines in adjacent positions; Eo, eosinophils; iDC, immature dendritic cells; MC, mast cells; mDCs, mature dendritic cells; Mo, monocytes; Mø, macrophages; NK, natural killer cells; PMN, neutrophils; T act, activated T cells; T naive, naive T cells; T muc, mucosal-homing T cells; Treg, regulatory T cells; T skin, skin-homing T cells.
It is now very clear that a large number of downstream effectors molecules that are regulated by chemokines are highly involved in the pathobiology of tumors. However, role of various effectors of chemokine receptors in primary and metastatic tumors are not well established. Moreover, chemokine signaling has been predominantly investigated in leukocytes and very little evidence is available on signaling cascades mediated by the chemokines in other cell types.
Although at the present, relatively little is known regarding the signaling pathways activated by chemokines in cancer cells, preliminary data show that CXCR4 and CCR7 are capable of activating a number of different intracellular events such as chemotaxis, invasion and adhesion, which are essential for cancer cells to achieve metastatic goal.
In non-metastatic breast cancer cells, actin polymerization and chemotactic responses are not induced, when CXCR4 and CXCR7 is stimulated with their ligands. Therefore it is possible that the signaling intermediates further upstream of these events are disrupted. Chemokine signaling pathways are mediated through G-protein coupled receptors (GPCRs) and generally use the Gi subclass of G-proteins that results in the activation of the Gi subunit, which mediates the inhibition of adenyl cyclase-mediated cAMP production and the mobilization of intracellular calcium. Treatment with CXCL12 or CCL19 inhibits forskolin-induced adenyl cyclase-mediated cAMP in metastatic breast cancer cell lines but not in non-metastatic cells. Furthermore, chemokines induce Gi-dependent intracellular calcium mobilization in metastatic breast cancer cells are inhibited by Gi inhibitors and pertussis toxin.
In leucocytes, the subunit of the G-protein complex is responsible for the activation of numerous kinase cascades downstream of GPCRs. In metastatic breast cancer cells, a rapid and sustained activation of ERK1/2, IkB, JNK, Akt, p38MAPK and GSK-3 / are observed in response to CXCR4 and CCR7 ligands, where as little or no activation detected in the non-metastatic cell lines. Several of these effector molecules play a significant role during the migration of leukocytes, these data imply that breast cancer cells use similar chemokine mediated mechanisms to regulate migration, proliferation and survival required for cancer progression and metastasis. Moreover, G-dependent signaling is not activated in the non-metastatic cell types, suggesting the blocked in functional signaling in further upstream of these signaling intermediates. Overall, the analysis of chemokine-mediated signaling events downstream of the G-protein and subunits in breast cancer cells suggests that the blockade in CXCR4 and CCR7 function in non-metastatic cells occurs at the level of G protein activation.
The heterotrimeric G proteins act as molecular switches in signaling pathways by coupling the activation of heptahelical receptors at the cell surface to intracellular responses. This role depends on the ability of the G subunit to cycle between a resting conformation primed for interaction with an activated receptor and a signaling conformation capable of modulating the activity of downstream effector proteins. In the resting state, the G subunit binds GDP and G. Receptors activate G proteins by catalysing GTP for GDP exchange on the G subunit, leading to a conformational change in the G and G subunits that allows their dissociation and activation of a variety of downstream effector proteins. The G protein returns to the resting conformation following GTP hydrolysis and subunit re-association.
Analysis of the chemokine receptor and G-protein coupling in resting and chemokine-activated metastatic and non-metastatic breast cancer cells demonstrated that CXCR4 and CCR7 forms complexes with the Gi subunit constitutively in both cell types. However, following chemokine stimulation, dissociation of Gi from the receptor takes place only in the metastatic cells. In parallel, the G subunit associated with chemokine receptors in both non-invasive and metastatic breast cancer cells; however, the dissociation of G from the receptor upon ligand stimulation occurred only in the metastatic cells. Further investigations revealed that the formation of the heterotrimeric G-protein complex could only be detected in the invasive cell types that express functional chemokine receptors. The differences in Gi and G binding observed throughout the panel of breast cancer cells lines were not due to the absence of G protein since all cells examined expressed G subunits. Therefore, this novel finding indicates that in non-invasive cells with non-functional CXCR4 or CCR7, Gi and G do not form the functional heterotrimeric complex, which is critical for GDP to GTP transfer and activation of signaling pathways downstream of G proteins.
Furthermore, these findings strongly suggest the existence of specific regulatory mechanisms that may be switched on or off during the metastatic progression and acquisition of an invasive phenotype. The hypothetical functional “on-switch” for chemokine receptors expressed in breast cancer cells is controlled at the level of the chemokine receptor (i.e. CXCR4 and/or CCR7) and G-protein subunit interactions. The lack of G-protein heterotrimeric complex formation in the non-invasive cells may be due to the expression of “incompatible” and subunits. It is noteworthy that the family of heterotrimeric G proteins consists of 27, 5 and 14 subunits, which may leads to a very high number of possible subunit combinations of varying affinity for a multitude of GPCRs. Another plausible explanation for the inability of G and G subunits to form stable complexes in selective cell lines may be due to the expression of one or more inhibitory molecules. Many aspects of G-protein-mediated signaling remain to be elucidated, and to gain a broader understanding of the functional roles of chemokine receptor signaling pathways in human breast and other cancer cells. Additional studies are necessary to delineate the regulation of G-proteins downstream of CXCR4 and CCR7. A detailed understanding of the physiological and pathophysiological role of G-protein-mediated signaling in normal and transformed cells will allow the full exploitation of this multifaceted signaling system as a target for pharmacological interventions.
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