-
International Journal of Molecular... Jan 2021Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating... (Review)
Review
Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors-CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (T) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.
Topics: Chemokines, CXC; Chemotactic Factors; Cytokines; Endothelial Cells; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Microcirculation; NF-kappa B p50 Subunit; Neoplasms; Receptors, CXCR
PubMed: 33467722
DOI: 10.3390/ijms22020843 -
Clinical Cancer Research : An Official... Nov 2008Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple... (Review)
Review
Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein-coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the level of translation, and/or (c) effect the organization of the cell cytoskeleton through posttranslational regulation of regulatory proteins. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models. Recently, IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells. In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention in targeting the tumor microenvironment.
Topics: Cell Movement; Cell Proliferation; Chemokines, CXC; Gene Expression Regulation; Humans; Interleukin-8; Models, Biological; Neoplasms; Neovascularization, Pathologic; Signal Transduction
PubMed: 18980965
DOI: 10.1158/1078-0432.CCR-07-4843 -
Targetable Brg1-CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking.EMBO Molecular Medicine Mar 2023Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement...
Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma-related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression was elevated in mouse models of ALD, in hepatocyte exposed to alcohol, and in human ALD specimens. Manipulation of Brg1 expression in hepatocytes influenced the development of ALD in mice. Flow cytometry showed that Brg1 deficiency specifically attenuated hepatic infiltration of Ly6G neutrophils in the ALD mice. RNA-seq identified C-X-C motif chemokine ligand 14 (CXCL14) as a potential target for Brg1. CXCL14 knockdown alleviated whereas CXCL14 over-expression enhanced ALD pathogenesis in mice. Importantly, pharmaceutical inhibition of Brg1 with a small-molecule compound PFI-3 or administration of an antagonist to the CXCL14 receptor ameliorated ALD pathogenesis in mice. Finally, a positive correlation between Brg1 expression, CXCL14 expression, and neutrophil infiltration was detected in ALD patients. In conclusion, our data provide proof-of-concept for targeting the Brg1-CXCL14 axis in ALD intervention.
Topics: Animals; Humans; Mice; Chemokines, CXC; Disease Models, Animal; Hepatocytes; Liver; Neutrophils; Liver Diseases, Alcoholic
PubMed: 36722664
DOI: 10.15252/emmm.202216592 -
Immunity Dec 2006In the bone marrow, the special microenvironment niches nurture a pool of hematopoietic stem cells (HSCs). Many HSCs reside near the vasculature, but the molecular...
In the bone marrow, the special microenvironment niches nurture a pool of hematopoietic stem cells (HSCs). Many HSCs reside near the vasculature, but the molecular regulatory mechanism of niches for HSC maintenance remains unclear. Here we showed that the induced deletion of CXCR4, a receptor for CXC chemokine ligand (CXCL) 12 in adult mice, resulted in severe reduction of HSC numbers and increased sensitivity to myelotoxic injury, although it did not impair expansion of the more mature progenitors. Most HSCs were found in contact with the cells expressing high amounts of CXCL12, which we have called CXCL12-abundant reticular (CAR) cells. CAR cells surrounded sinusoidal endothelial cells or were located near the endosteum. CXCL12-CXCR4 signaling plays an essential role in maintaining the quiescent HSC pool, and CAR cells appear to be a key component of HSC niches, including both vascular and endosteal niches in adult bone marrow.
Topics: Adoptive Transfer; Animals; Bone Marrow; Chemokine CXCL12; Chemokines, CXC; Flow Cytometry; Hematopoietic Stem Cells; Immunohistochemistry; Mice; Mice, Mutant Strains; Receptors, CXCR4; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stromal Cells
PubMed: 17174120
DOI: 10.1016/j.immuni.2006.10.016 -
World Journal of Gastroenterology Feb 2014Gastric cancer is the fourth most common cancer, and the second-highest cause of cancer-related deaths worldwide. Despite extensive research to identify novel diagnostic... (Review)
Review
Gastric cancer is the fourth most common cancer, and the second-highest cause of cancer-related deaths worldwide. Despite extensive research to identify novel diagnostic and therapeutic agents, patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis, and treatment is dependent mainly on conventional cytotoxic chemotherapy. To improve the quality of life and survival of gastric cancer patients, a better understanding of the underlying molecular pathologies, and their application towards the development of novel targeted therapies, is urgently needed. Chemokines are a group of small proteins associated with cytoskeletal rearrangements, the directional migration of several cell types during development and physiology, and the host immune response via interactions with G-protein coupled receptors. There is also growing evidence to suggest that chemokines not only play a role in the immune system, but are also involved in the development and progression of tumors. In gastric cancer, CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment. CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation, survival, growth, invasion and metastasis, as well as indirectly by regulating angiogenesis, and tumor-leukocyte interactions. In this review, we will focus on the roles of CXC chemokines and their receptors in the development, progression, and metastasis of gastric tumors, and discuss their therapeutic potential for gastric cancer.
Topics: Carcinoma; Cell Survival; Cell Transformation, Neoplastic; Chemokines, CXC; Disease Progression; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Prognosis; Quality of Life; Receptors, Chemokine; Stomach; Stomach Neoplasms; Treatment Outcome; Tumor Microenvironment
PubMed: 24587647
DOI: 10.3748/wjg.v20.i7.1681 -
Hepatology (Baltimore, Md.) Oct 2011The process of liver repair and regeneration following hepatic injury is complex and relies on a temporally coordinated integration of several key signaling pathways.... (Comparative Study)
Comparative Study Review
The process of liver repair and regeneration following hepatic injury is complex and relies on a temporally coordinated integration of several key signaling pathways. Pathways activated by members of the CXC family of chemokines play important roles in the mechanisms of liver repair and regeneration through their effects on hepatocytes. However, little is known about the signaling pathways used by CXC chemokine receptors in hepatocytes. Here we review our current understanding of the pathways involved in both CXC chemokine receptor signaling in other cell types, most notably neutrophils, and similar pathways operant during hepatocyte proliferation/liver regeneration to formulate a basis for the function of CXC chemokine receptor signaling in hepatocytes.
Topics: Animals; Chemokine CXCL2; Chemokines, CXC; Hepatocytes; Humans; Liver Diseases; Liver Regeneration; Receptors, Chemokine; Sensitivity and Specificity; Signal Transduction
PubMed: 21626524
DOI: 10.1002/hep.24457 -
Current Pharmaceutical Design 2014Chemokines are a family of chemotactic cytokines that play an essential role in leukocyte trafficking. Upregulation of both CC and CXC chemokines is a hallmark of the... (Review)
Review
Chemokines are a family of chemotactic cytokines that play an essential role in leukocyte trafficking. Upregulation of both CC and CXC chemokines is a hallmark of the inflammatory and reparative response following myocardial infarction. Release of danger signals from dying cells and damaged extracellular matrix activates innate immune pathways that stimulate chemokine synthesis. Cytokineand chemokine-driven adhesive interactions between endothelial cells and leukocytes mediate extravasation of immune cells into the infarct. CXC chemokines (such as interleukin-8) are bound to glycosaminoglycans on the endothelial surface and activate captured neutrophils, inducing expression of integrins. CC chemokines (such as monocyte chemoattractant protein (MCP)-1) mediate recruitment of proinflammatory and phagocytotic mononuclear cells into the infarct. CC Chemokines may also regulate late infiltration of the healing infarct with inhibitory leukocytes that suppress inflammation and restrain the post-infarction immune response. Non-hematopoietic cells are also targeted by chemokines; in healing infarcts, the CXC chemokine Interferon-γ inducible Protein (IP)-10 exerts antifibrotic actions, inhibiting fibroblast migration. Another member of the CXC subfamily, Stromal cell-derived Factor (SDF)-1, may protect the infarcted heart by activating pro-survival signaling in cardiomyocytes, while exerting angiogenic actions through chemotaxis of endothelial progenitors. Several members of the chemokine family may be promising therapeutic targets to attenuate adverse remodeling in patients with myocardial infarction.
Topics: Animals; Chemokine CXCL12; Chemokines; Chemokines, CXC; Drug Delivery Systems; Humans; Myocardial Infarction
PubMed: 23844733
DOI: 10.2174/13816128113199990449 -
Journal of Leukocyte Biology Jul 2000A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their... (Review)
Review
A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.
Topics: Amino Acid Motifs; Angiogenesis Inhibitors; Animals; Arthritis, Rheumatoid; Chemokine CXCL10; Chemokines, CXC; Chronic Disease; Fibrosis; Humans; Inflammation; Interleukin-8; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Pulmonary Fibrosis; Receptors, Chemokine; Structure-Activity Relationship
PubMed: 10914483
DOI: No ID Found -
Frontiers in Immunology 2018Chemokines govern leukocyte migration by attracting cells that express their cognate ligands. Many cancer types show altered chemokine secretion profiles, favoring the... (Review)
Review
Chemokines govern leukocyte migration by attracting cells that express their cognate ligands. Many cancer types show altered chemokine secretion profiles, favoring the recruitment of pro-tumorigenic immune cells and preventing the accumulation of anti-tumorigenic effector cells. This can ultimately result in cancer immune evasion. The manipulation of chemokine and chemokine-receptor signaling can reshape the immunological phenotypes within the tumor microenvironment in order to increase the therapeutic efficacy of cancer immunotherapy. Here we discuss the three chemokine-chemokine receptor axes, CXCR1/2-CXCL1-3/5-8, CXCR3-CXCL9/10/11, and CXCR4-CXCL12 and their role on pro-tumorigenic immune cells and anti-tumorigenic effector cells in solid tumors. In particular, we summarize current strategies to target these axes and discuss their potential use in treatment approaches.
Topics: Carcinogenesis; Chemokines, CXC; Humans; Immunity, Cellular; Immunotherapy; Lymphocytes; Macrophages; Myeloid-Derived Suppressor Cells; Neoplasm Invasiveness; Neoplasms; Receptors, CXCR; Tumor Escape; Tumor Microenvironment
PubMed: 30319622
DOI: 10.3389/fimmu.2018.02159 -
BMC Medical Genomics Apr 2022The prognosis of pancreatic cancer is poor, with a 5-year survival rate of less than 10%. Studies have shown that chemokines in the tumour microenvironment are often...
BACKGROUND
The prognosis of pancreatic cancer is poor, with a 5-year survival rate of less than 10%. Studies have shown that chemokines in the tumour microenvironment are often altered, which is associated with immune infiltration and the prognosis and survival of pancreatic cancer patients.
METHODS
Multiomics and bioinformatics tools were used to clarify CXC chemokine expression and its role in the pancreatic ductal adenocarcinoma (PDAC) immune microenvironment.
RESULTS
Most CXC chemokines were upregulated in pancreatic cancer and correlated with patient prognosis. CXC chemokines can activate cancer-related signalling pathways and affect immune infiltration. Furthermore, most CXC chemokines were significantly correlated with the abundance of macrophages, neutrophils and dendritic cells. CXCL5 was selected as a hub gene, and a variety of immune checkpoints, including PD-1/PD-L1 and CTLA-4, were identified.
CONCLUSION
Our study provides novel insights into CXC chemokine expression and its role in the PDAC immune microenvironment. These results can provide more data about prognostic biomarkers and therapeutic targets of PDAC.
Topics: Carcinoma, Pancreatic Ductal; Chemokines, CXC; Humans; Pancreatic Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 35468838
DOI: 10.1186/s12920-022-01246-4