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Chemokines in Cancer and Inflammatory Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 69788

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Prof. Dr. Paul Proost

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Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Herestraat 49 box 1042, B-3000 Leuven, Belgium
Interests: chemokines; posttranslational modification; chemokine-glycosaminoglycan interactions; chemokine signaling properties; chemokines in disease

Prof. Dr. Flavio A. Amaral

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Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Interests: arthritis; chemokine; resolution of inflammation; inflammatory pain
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Dear Colleagues,

Chemokines are critical mediators during homeostatic and pathological conditions, controlling cellular proliferation, differentiation, movement, and activation. The chemokine biology is a complex system that is regulated at multiple levels including ligand and receptor expression in tissues, interaction with glycosaminoglycans, biased signaling through G protein-coupled receptors, synergy between chemoattractants and posttranslational modifications of chemokines and chemokine receptors. In an inflammatory environment, chemokines have a major function in controlling leukocyte migration in the productive and the resolving phases of inflammation. Besides their active participation in acute and chronic inflammatory disorders, some chemokine have angiogenic or fibrotic properties. In addition, in cancer immunity, chemokines shape the tumor microenvironment by controlling the accumulation of different cellular populations that impact on tumor progression. Therefore, detailed knowledge on the activity of the chemokine system during pathological situations is essential for the development of new strategies to treat diseases targeting this chemokine system. Here, we invite authors to submit studies on the role of chemokines in homeostasis, inflammation or cancer.

Prof. Dr. Paul Proost
Prof. Dr. Flavio A. Amaral
Guest Editors

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Keywords

Chemokines
Inflammation
Cancer
Infection
Angiogenesis
Fibrosis
Hematopoiesis

Related Special Issue

Regulation of Chemokine-Receptor Interactions and Functions in International Journal of Molecular Sciences (13 articles)

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16 pages, 7442 KiB

Open AccessArticle

The Chemokine CXCL16 Is a New Biomarker for Lymph Node Analysis of Colon Cancer Outcome

by Manar AbdelMageed, Haytham Ali, Lina Olsson, Gudrun Lindmark, Marie-Louise Hammarström, Sten Hammarström and Basel Sitohy

Int. J. Mol. Sci. 2019, 20(22), 5793; https://doi.org/10.3390/ijms20225793 - 18 Nov 2019

Cited by 16 | Viewed by 3612

Abstract

Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient’s survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(−) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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12 pages, 1874 KiB

Open AccessArticle

Serum Levels of Interleukin-6 and Titers of Antibodies against Porphyromonas gingivalis Could Be Potential Biomarkers for the Diagnosis of Oral Squamous Cell Carcinoma

by Dae-Gun Park, Bok Hee Woo, Byung-Joo Lee, Sanggyeong Yoon, Youngseuk Cho, Yong-Deok Kim, Hae Ryoun Park and Jae Min Song

Int. J. Mol. Sci. 2019, 20(11), 2749; https://doi.org/10.3390/ijms20112749 - 04 Jun 2019

Cited by 19 | Viewed by 3598

Abstract

It has been suggested that Porphyromonas gingivalis (P. gingivalis), a keystone pathogen in chronic periodontitis, is associated with a variety of cancers, including oral cancer. Recently, studies have shown the effects of persistent exposure to P. gingivalis on the promotion of tumorigenic properties of oral epithelial cells, suggesting that chronic P. gingivalis infection is a potential risk factor for oral cancer. On the other hand, Fusobacterium nucleatum (F. nucleatum), one of the major periodontal pathogens, has emerged as an important factor in the colon cancer progression. Here, we investigated the diagnostic potential of serum immunoglobulin G antibody against periodontal pathogens, P. gingivalis and F. nucleatum, and serum IL-6 for oral squamous cell carcinoma (OSCC). An enzyme-linked immunosorbent assay (ELISA) was used to determine and compare the serum levels of interleukin 6 (IL-6), F. nucleatum IgG, and P. gingivalis IgG in 62 OSCC patients with 46 healthy controls. The serum levels of P. gingivalis IgG and IL-6 were higher in OSCC patients than in non-OSCC controls, and the difference was statistically significant. In addition, a high serum level of IL-6 was associated with a worse prognosis in OSCC patients. Thus, P. gingivalis IgG and IL-6 could be utilized as potential serum biomarkers for the diagnosis of OSCC, and the serum level of IL-6 contributes to improved prognostic performance. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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17 pages, 4116 KiB

Open AccessArticle

Engineering of Nanobodies Recognizing the Human Chemokine Receptor CCR7

by Barbara D. Jakobs, Lisa Spannagel, Vladimir Purvanov, Edith Uetz-von Allmen, Christoph Matti and Daniel F. Legler

Int. J. Mol. Sci. 2019, 20(10), 2597; https://doi.org/10.3390/ijms20102597 - 27 May 2019

Cited by 11 | Viewed by 4279

Abstract

The chemokine receptor CCR7 plays a pivotal role in health and disease. In particular, CCR7 controls homing of antigen-bearing dendritic cells and T cells to lymph nodes, where adaptive immune responses are initiated. However, CCR7 also guides T cells to inflamed synovium and thereby contributes to rheumatoid arthritis and promotes cancer cell migration and metastasis formation. Nanobodies have recently emerged as versatile tools to study G-protein-coupled receptor functions and are being tested in diagnostics and therapeutics. In this study, we designed a strategy to engineer novel nanobodies recognizing human CCR7. We generated a nanobody library based on a solved crystal structure of the nanobody Nb80 recognizing the β₂-adrenergic receptor (β₂AR) and by specifically randomizing two segments within complementarity determining region 1 (CDR1) and CDR3 of Nb80 known to interact with β₂AR. We fused the nanobody library to one half of split-YFP in order to identify individual nanobody clones interacting with CCR7 fused to the other half of split-YFP using bimolecular fluorescence complementation. We present three novel nanobodies, termed Nb1, Nb5, and Nb38, that recognize human CCR7 without interfering with G-protein-coupling and downstream signaling. Moreover, we were able to follow CCR7 trafficking upon CCL19 triggering using Nb1, Nb5, and Nb38. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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11 pages, 1852 KiB

Open AccessArticle

Oral Administration of Porphyromonas gingivalis, a Major Pathogen of Chronic Periodontitis, Promotes Resistance to Paclitaxel in Mouse Xenografts of Oral Squamous Cell Carcinoma

by Jae Min Song, Bok Hee Woo, Ji Hye Lee, Sanggyeong Yoon, Youngseuk Cho, Yong-Deok Kim and Hae Ryoun Park

Int. J. Mol. Sci. 2019, 20(10), 2494; https://doi.org/10.3390/ijms20102494 - 21 May 2019

Cited by 17 | Viewed by 3155

Abstract

Chemotherapy is not a first-line therapy for oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer, because most OSCC shows resistance to chemotherapeutic reagents. Inflammatory signals are suggested to be associated with chemoresistance as well as carcinogenesis in many different cancers, and thus chronic periodontitis, the most common chronic inflammatory disease of the oral cavity, could modulate responsiveness to chemotherapeutic agents used against oral cancer. This study was performed to define the role of chronic periodontitis in oral cancer progression and to determine the responsiveness of oral cancer to a chemotherapeutic reagent. First, we quantified the tumor growth rate and changes in serum cytokine profiles of mice administered Porphyromonas gingivalis, a major pathogen of chronic periodontitis. Compared with uninfected mice, the mice that were chronically administered P. gingivalis showed increased resistance to paclitaxel and a decreased tumor growth rate. In addition, P. gingivalis-treated mice exhibited higher serum levels of interleukin-6 (IL-6) than uninfected mice. Furthermore, the sensitivity of tumor xenografts to paclitaxel in mice administered P. gingivalis was dramatically increased when the mice were administered ibuprofen, an anti-inflammatory drug which supports the modulatory effect of periodontal pathogen-induced inflammation in chemoresistance. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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16 pages, 3764 KiB

Open AccessArticle

Monocyte Chemoattractant Protein-1, a Possible Biomarker of Multiorgan Failure and Mortality in Ventilator-Associated Pneumonia

by Yia-Ting Li, Yao-Chen Wang, Hsiang-Lin Lee, Su-Chin Tsao, Min-Chi Lu and Shun-Fa Yang

Int. J. Mol. Sci. 2019, 20(9), 2218; https://doi.org/10.3390/ijms20092218 - 06 May 2019

Cited by 10 | Viewed by 3080

Abstract

Ventilator-associated pneumonia (VAP) leads to increased patients’ mortality and medical expenditure. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the pathogenesis of lung inflammation and infection. Therefore, the plasma concentration of MCP-1 was assessed and correlated with the clinical course in VAP patients. This retrospective observational study recruited 45 healthy volunteers, 12 non-VAP subjects, and 30 VAP patients. The diagnostic criteria for VAP were based on the American Thoracic Society guidelines, and the level of plasma MCP-1 was determined by ELISA. Plasma MCP-1 concentration was significantly elevated in the acute stage in VAP patients when compared with the control (p < 0.0001) and non-VAP patient groups (p = 0.0006). Subsequently, it was remarkably decreased following antibiotic treatment. Moreover, plasma MCP-1 concentration was positively correlated with indices of pulmonary dysfunction, including the lung injury score (p = 0.02) and the oxygenation index (p = 0.02). When patients with VAP developed adult respiratory distress syndrome (ARDS), their plasma MCP-1 concentrations were significantly higher than those of patients who did not develop ARDS (p = 0.04). Moreover, plasma MCP-1 concentration was highly correlated with organ failure scores, including simplified acute physiology score II (SAPS II, p < 0.0001), sequential organ failure assessment score (SOFA, p < 0.0001), organ dysfunctions and/or infection (ODIN, p < 0.0001), predisposition, insult response and organ dysfunction (PIRO, p = 0.005), and immunodeficiency, blood pressure, multilobular infiltrates on chest radiograph, platelets and hospitalization 10 days before onset of VAP (IBMP-10, p = 0.004). Our results demonstrate that plasma MCP-1 is an excellent marker for recognizing VAP when the cut-off level is set to 347.18 ng/mL (area under the curve (AUC) = 0.936, 95% CI = 0.863–0.977). In conclusion, MCP-1 not only could be a biological marker related to pulmonary dysfunction, organ failure, and mortality in patients with VAP, but also could be used for early recognition of VAP. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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13 pages, 1701 KiB

Open AccessArticle

Pro-Inflammatory Stimuli Influence Expression of Intercellular Adhesion Molecule 1 in Human Anulus Fibrosus Cells through FAK/ERK/GSK3 and PKCδ Signaling Pathways

by Bor-Ren Huang, Da-Tian Bau, Tzu-Sheng Chen, I-Chen Chuang, Cheng-Fang Tsai, Pei-Chun Chang, Horng-Chaung Hsu and Dah-Yuu Lu

Int. J. Mol. Sci. 2019, 20(1), 77; https://doi.org/10.3390/ijms20010077 - 25 Dec 2018

Cited by 11 | Viewed by 3345

Abstract

Objective: Intervertebral disc (IVD) degeneration and disc herniation are major causes of lower back pain, which involve the presence of inflammatory mediators and tissue invasion by immune cells. Intercellular adhesion molecule 1 (ICAM1, also termed CD54) is an adhesion molecule that mediates cell-cell interactions, particularly between immune cells and target tissue. The aim of this study was to examine the intracellular signaling pathways involved in inflammatory stimuli-induced ICAM1 expression in human anulus fibrosus (AF) cells. Methods: Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and flow cytometry were performed to dissect the roles of different signaling pathways in inflammatory stimuli-mediated ICAM1 expression. Results: Using qPCR and western blot analyses, a significant increase in ICAM1 expression was observed in AF cells after stimulation of lipopolysaccharide (LPS) plus interferon-gamma (IFNγ) in a time-dependent manner. Flow cytometry revealed ICAM1 upregulation on the surface of AF cells. Importantly, LPS plus IFNγ treatment also significantly promoted Chemokine ligand (CCL)2 expression, but not CCL3. The enhanced ICAM1 expression was abolished after incubation with antibody against CCL2. In AF cells, treatment with LPS plus IFNγ activated the FAK/ERK/GSK3 signaling pathways, promoted a time-dependent increase in PKCδ phosphorylation, and promoted PKCδ translocation to the nucleus. Treatment with the pharmacological PKCδ inhibitor; rottlerin, effectively blocked the enhanced productions of ICAM1 and CCL2. Conclusions: Inflammatory stimuli in AF cells are part of a specific pathophysiology in IVD degeneration and disc herniation that modulates CCL2/ICAM1 activation through the FAK/ERK/GSK3 and PKCδ signaling pathways in AF cells. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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15 pages, 5757 KiB

Open AccessArticle

Fluorescently Tagged CCL19 and CCL21 to Monitor CCR7 and ACKR4 Functions

by Vladimir Purvanov, Christoph Matti, Guerric P. B. Samson, Ilona Kindinger and Daniel F. Legler

Int. J. Mol. Sci. 2018, 19(12), 3876; https://doi.org/10.3390/ijms19123876 - 04 Dec 2018

Cited by 19 | Viewed by 4783

Abstract

Chemokines are essential guidance cues orchestrating cell migration in health and disease. Cognate chemokine receptors sense chemokine gradients over short distances to coordinate directional cell locomotion. The chemokines CCL19 and CCL21 are essential for recruiting CCR7-expressing dendritic cells bearing pathogen-derived antigens and lymphocytes to lymph nodes, where the two cell types meet to launch an adaptive immune response against the invading pathogen. CCR7-expressing cancer cells are also recruited by CCL19 and CCL21 to metastasize in lymphoid organs. In contrast, atypical chemokine receptors (ACKRs) do not transmit signals required for cell locomotion but scavenge chemokines. ACKR4 is crucial for internalizing and degrading CCL19 and CCL21 to establish local gradients, which are sensed by CCR7-expressing cells. Here, we describe the production of fluorescently tagged chemokines by fusing CCL19 and CCL21 to monomeric red fluorescent protein (mRFP). We show that purified CCL19-mRFP and CCL21-mRFP are versatile and powerful tools to study CCR7 and ACKR4 functions, such as receptor trafficking and chemokine scavenging, in a spatiotemporal fashion. We demonstrate that fluorescently tagged CCL19 and CCL21 permit the visualization and quantification of chemokine gradients in real time, while CCR7-expressing leukocytes and cancer cells sense the guidance cues and migrate along the chemokine gradients. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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18 pages, 3556 KiB

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Differential Effects of Posttranslational Modifications of CXCL8/Interleukin-8 on CXCR1 and CXCR2 Internalization and Signaling Properties

by Alessandro Vacchini, Anneleen Mortier, Paul Proost, Massimo Locati, Mieke Metzemaekers and Elena Monica Borroni

Int. J. Mol. Sci. 2018, 19(12), 3768; https://doi.org/10.3390/ijms19123768 - 27 Nov 2018

Cited by 14 | Viewed by 4641

Abstract

CXCL8 or interleukin (IL)-8 directs neutrophil migration and activation through interaction with CXCR1 and CXCR2 that belong to the family of G protein-coupled receptors (GPCRs). Naturally occurring posttranslational modifications of the NH₂-terminal region of CXCL8 affect its biological activities, but the underlying molecular mechanisms are only partially understood. Here, we studied the implications of site-specific citrullination and truncation for the signaling potency of CXCL8. Native CXCL8(1-77), citrullinated [Cit5]CXCL8(1-77) and the major natural isoform CXCL8(6-77) were chemically synthesized and tested in internalization assays using human neutrophils. Citrullinated and truncated isoforms showed a moderately enhanced capacity to induce internalization of CXCR1 and CXCR2. Moreover, CXCL8-mediated activation of Gα_i-dependent signaling through CXCR1 and CXCR2 was increased upon modification to [Cit5]CXCL8(1-77) or CXCL8(6-77). All CXCL8 variants promoted recruitment of β-arrestins 1 and 2 to CXCR1 and CXCR2. Compared to CXCL8(1-77), CXCL8(6-77) showed an enhanced potency to recruit β-arrestin 2 to both receptors, while for [Cit5]CXCL8(1-77) only the capacity to induce β-arrestin 2 recruitment to CXCR2 was increased. Both modifications had no biasing effect, i.e., did not alter the preference of CXCL8 to activate either Gα_i-protein or β-arrestin-dependent signaling through its receptors. Our results support the concept that specific chemokine activities are fine-tuned by posttranslational modifications. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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18 pages, 3152 KiB

Open AccessArticle

Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12

by Irene del Molino del Barrio, Georgina C. Wilkins, Annette Meeson, Simi Ali and John A. Kirby

Int. J. Mol. Sci. 2018, 19(11), 3592; https://doi.org/10.3390/ijms19113592 - 14 Nov 2018

Cited by 18 | Viewed by 5551 | Correction

Abstract

Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has been shown to promote breast cancer progression. This process, however, can be affected by the expression of the atypical chemokine receptor ACKR3. Given ACKR3’s ability to form heterodimers with CXCR4, we investigated how dual expression of both receptors differed from their lone expression in terms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinese hamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation was assessed and correlated with receptor internalization. Functional consequences in cell migration and proliferation were determined through wound healing assays and calcium flux. Initial experiments showed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 and ACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4’s Akt activation after CXCL12’s stimulation but not ERK phosphorylation (p < 0.05). To assess this signalling disparity, receptor internalization was assessed and it was observed that ACKR3 was recycled to the surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with a proteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207, which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001), highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but not ACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co-expression could increase cellular migration (p < 0.01). These findings suggest that both receptors can signal through ERK and Akt pathways but co-expression can alter their kinetics and internalization pathways. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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13 pages, 998 KiB

Open AccessReview

Chemokine Signaling in Chemotherapy-Induced Neuropathic Pain

by Laura Brandolini, Michele d’Angelo, Andrea Antonosante, Annamaria Cimini and Marcello Allegretti

Int. J. Mol. Sci. 2019, 20(12), 2904; https://doi.org/10.3390/ijms20122904 - 14 Jun 2019

Cited by 67 | Viewed by 6585

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of chemotherapics such as taxanes, vinca alkaloids, and platinum compounds. In recent years, several reports have indicated the involvement of different molecular mechanisms in CIPN. The pathways described so far are diverse and target various components of the peripheral Nervous System (PNS). Among the contributors to neuropathic pain, inflammation has been indicated as a powerful driver of CIPN. Several pieces of evidence have demonstrated a chemotherapy-induced increase in peripheral pro-inflammatory cytokines and a strong correlation with peripheral neuropathy. At present, there are not adequate strategies to prevent CIPN, although there are drugs for treating CIPN, such as duloxetine, that have displayed a moderate effect on CIPN. In this review, we focus on the players involved in CIPN with a particular emphasis on chemokine signaling. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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26 pages, 2238 KiB

Open AccessReview

Chemokines in COPD: From Implication to Therapeutic Use

by Pauline Henrot, Renaud Prevel, Patrick Berger and Isabelle Dupin

Int. J. Mol. Sci. 2019, 20(11), 2785; https://doi.org/10.3390/ijms20112785 - 06 Jun 2019

Cited by 62 | Viewed by 6884

Abstract

Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chemokine receptors. Here, we provide an overview of the evidence regarding chemokines involvement in COPD, and we hypothesize that a dysregulation of this tightly regulated system is critical in COPD evolution, both at a stable state and during exacerbations. Targeting chemokines and chemokine receptors could be highly attractive as a mean to control both chronic inflammation and bronchial remodeling. We present a special focus on the CXCL8-CXCR1/2, CXCL9/10/11-CXCR3, CCL2-CCR2, and CXCL12-CXCR4 axes that seem particularly involved in the disease pathophysiology. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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13 pages, 1648 KiB

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C-X-C Motif Chemokine Ligand 14 is a Unique Multifunctional Regulator of Tumor Progression

by Xiao-Yan Yang, Shigeyuki Ozawa, Yasumasa Kato, Yojiro Maehata, Kazuhito Izukuri, Takeharu Ikoma, Keisuke Kanamori, Tetsu Akasaka, Kenji Suzuki, Hiroshi Iwabuchi, Shun-Ichi Kurata, Iyoko Katoh, Takashi Sakurai, Tohru Kiyono and Ryu-Ichiro Hata

Int. J. Mol. Sci. 2019, 20(8), 1872; https://doi.org/10.3390/ijms20081872 - 16 Apr 2019

Cited by 14 | Viewed by 3634

Abstract

Cancer is a leading cause of death and disease worldwide, with a tremendous financial impact. Thus, the development of cost-effective novel approaches for suppressing tumor growth and progression is essential. In an attempt to identify the mechanisms responsible for tumor suppression, we screened for molecules downregulated in a cancer progression model and found that the chemokine CXCL14, also called BRAK, was the most significantly downregulated. Increasing the production of CXCL14 protein by transfecting tumor cells with a CXCL14 expression vector and transplanting the cells into the back skin of immunodeficient mice suppressed tumor cell growth compared with that of parental tumor cells, suggesting that CXCL14 suppressed tumor growth in vivo. However, some studies have reported that over-expression of CXCL14, especially in stromal cells, stimulated the progression of tumor formation. Transgenic mice expressing 10-fold more CXCL14 protein than wild-type C57BL/6 mice showed reduced rates of chemical carcinogenesis, transplanted tumor growth, and metastasis without apparent side effects. CXCL14 also acts as an antimicrobial molecule. In this review, we highlight recent studies involving the identification and characterization of CXCL14 in cancer progression and discuss the reasons for the context-dependent effects of CXCL14 on tumor formation. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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27 pages, 7844 KiB

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Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization

by Elisabetta Marcuzzi, Roberta Angioni, Barbara Molon and Bianca Calì

Int. J. Mol. Sci. 2019, 20(1), 96; https://doi.org/10.3390/ijms20010096 - 27 Dec 2018

Cited by 106 | Viewed by 10094 | Correction

Abstract

Metastasis still represents the primary cause of cancer morbidity and mortality worldwide. Chemokine signalling contributes to the overall process of cancer growth and metastasis, and their expression in both primary tumors and metastatic lesions correlate with prognosis. Chemokines promote tumor metastasization by directly supporting cancer cell survival and invasion, angiogenesis, and by indirectly shaping the pre-metastatic niches and antitumor immunity. Here, we will focus on the relevant chemokine/chemokine receptor axes that have been described to drive the metastatic process. We elaborate on their role in the regulation of tumor angiogenesis and immune cell recruitment at both the primary tumor lesions and the pre-metastatic foci. Furthermore, we also discuss the advantages and limits of current pharmacological strategies developed to target chemokine networks for cancer therapy. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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17 pages, 915 KiB

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Adaptive Immunodeficiency in WHIM Syndrome

by Shamik Majumdar and Philip M. Murphy

Int. J. Mol. Sci. 2019, 20(1), 3; https://doi.org/10.3390/ijms20010003 - 20 Dec 2018

Cited by 23 | Viewed by 5840

Abstract

Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The “M” in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review. Full article

(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)

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