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Chemokines and Chemokine Receptors: New Targets for Cancer Therapy

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Special Issue Information
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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 30848

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Special Issue Editor

Dr. Rosa Marina Melillo

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Guest Editor

Department of Molecular Medicine and Medical Biotecnology, University of Naples Federico II, 80138 Naples, Italy
Interests: thyroid carcinoma; receptor tyrosine kinase; chemokine/chemokine receptor; signal transduction; cancer immunity and inflammation; cancer stem cells; gastric cancer

Special Issue Information

Dear Colleagues,

Chemokines are a large family of small cytokines (8–17 kDa), originally identified as chemoattractants for innate and adaptive immune cells, that regulate various immune-related physiological and pathological processes. Recently, chemokines have been found to exert a wider influence since they are expressed not only in immune cells but also in other cell types. Chemokines exert their biological activities by binding to chemokine receptors that belong to the G-protein coupled receptor (GPCR) family. Chemokine binding to the cognate receptor causes the activation of various signaling cascades that mediate, besides chemotaxis, such biological processes as cell proliferation, survival, and adhesion.

Chemokines are also involved in cancer. Indeed, chemokines and their receptors are often expressed by both cancer cells and stromal cells in the cancer microenvironment. Chemokines can act on cancer cells by enhancing proliferation, survival, stemness, motility, and invasiveness. These last two activities are critical in mediating tumor metastatization to specific body sites. On the other hand, chemokines can influence the composition and activity of tumoral stromal cells. Chemokines can indeed promote inflammation and angiogenesis in the tumoral stroma. Moreover, chemokines can shape the composition and the function of the cancer-associated immune system. Accordingly, the levels of specific chemokines have been used as predictive markers of overall and/or relapse-free survival in many cancer types.

Given their pleiotropic role in cancer, various therapeutic tools have been developed that target chemokines and/or their receptors. These tools include pharmacological inhibitors and antibodies. In many cancer models, the inhibition of chemokine circuits has shown significant anti-tumoral effects. For instance, CXCR4 or CXCR2 antagonism inhibits tumor growth and progression by acting both on tumoral cells and on the stroma, and clinical trials targeting these and other chemokine receptors are currently ongoing. This Special Issue will be focused on the role of chemokines in cancer, including the molecular mechanisms underlying chemokine protumorigenic activity, their use as potential predictive markers, and their role as targets for innovative single-agent or combinatorial therapies.

Prof. Dr. Rosa Marina Melillo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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16 pages, 3240 KiB

Open AccessArticle

New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer

by Crescenzo D’Alterio, Antonella Zannetti, Anna Maria Trotta, Caterina Ieranò, Maria Napolitano, Giuseppina Rea, Adelaide Greco, Piera Maiolino, Sandra Albanese, Giosuè Scognamiglio, Fabiana Tatangelo, Salvatore Tafuto, Luigi Portella, Sara Santagata, Guglielmo Nasti, Alessandro Ottaiano, Roberto Pacelli, Paolo Delrio, Gerardo Botti and Stefania Scala

Cancers 2020, 12(7), 1952; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071952 - 18 Jul 2020

Cited by 17 | Viewed by 3203

Abstract

The chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies. Full article

(This article belongs to the Special Issue Chemokines and Chemokine Receptors: New Targets for Cancer Therapy)

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22 pages, 3043 KiB

Open AccessArticle

Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients

by Qun Wang, Elisa Schmoeckel, Bernd P. Kost, Christina Kuhn, Aurelia Vattai, Theresa Vilsmaier, Sven Mahner, Doris Mayr, Udo Jeschke and Helene Hildegard Heidegger

Cancers 2019, 11(12), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11122004 - 12 Dec 2019

Cited by 25 | Viewed by 2585

Abstract

The chemokine CCL22 recruits regulatory T (T-reg) cells into tumor tissues and is expressed in many human tumors. However, the prognostic role of CCL22 in cervical cancer (CC) has not been determined. This study retrospectively analyzed the clinical significance of the expression of CCL22 and FOXP3 in 230 cervical cancer patients. Immunohistochemical staining analyses of CCL22 and FOXP3 were performed with a tissue microarray. Double immunofluorescence staining, cell coculture, and ELISA were used to determine CCL22 expressing cells and mechanisms. The higher number of infiltrating CCL22+ cells (CCL22^high) group was associated with lymph node metastasis (p = 0.004), Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stages (p = 0.010), therapeutic strategies (p = 0.007), and survival status (p = 0.002). The number of infiltrating CCL22+ cells was positively correlated with that of infiltrating FOXP3+ cells (r = 0.210, p = 0.001). The CCL22^high group had a lower overall survival rate (OS), compared to the CCL22^low group (p = 0.001). However, no significant differences in progression free survival (PFS) were noted between the two groups. CCL22^high was an independent predictor of shorter OS (HR, 4.985; p = 0.0001). The OS of the combination group CCL22^highFOXP3^high was significantly lower than that of the combination group CCL22^lowFOXP3^low regardless of the FIGO stage and disease subtype. CCL22^highFOXP3^high was an independent indictor of shorter OS (HR, 5.284; p = 0.009). The PFS of group CCL22^highFOXP3^high was significantly lower than that of group CCL22^lowFOXP3^low in cervical adenocarcinoma, but CCL22^highFOXP3^high was not an independent indicator (HR, 3.018; p = 0.068). CCL22 was primarily expressed in M2-like macrophages in CC and induced by cervical cancer cells. The findings of our study indicate that cervical cancer patients with elevated CCL22+ infiltrating cells require more aggressive treatment. Moreover, the results provide a basis for subsequent, comprehensive studies to advance the design of immunotherapy for cervical cancer. Full article

(This article belongs to the Special Issue Chemokines and Chemokine Receptors: New Targets for Cancer Therapy)

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Review

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18 pages, 2864 KiB

Open AccessReview

The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression

by Balsam Rizeq and Mohammed Imad Malki

Cancers 2020, 12(4), 1036; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12041036 - 23 Apr 2020

Cited by 58 | Viewed by 9975

Abstract

Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes. Full article

(This article belongs to the Special Issue Chemokines and Chemokine Receptors: New Targets for Cancer Therapy)

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25 pages, 799 KiB

Open AccessReview

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

by Ha Thi Thu Do, Chang Hoon Lee and Jungsook Cho

Cancers 2020, 12(2), 287; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020287 - 24 Jan 2020

Cited by 130 | Viewed by 9793

Abstract

Chemokines are chemotactic cytokines that mediate immune cell chemotaxis and lymphoid tissue development. Recent advances have indicated that chemokines and their cognate receptors play critical roles in cancer-related inflammation and cancer progression. On the basis of these findings, the chemokine system has become a new potential drug target for cancer immunotherapy. In this review, we summarize the essential roles of the complex network of chemokines and their receptors in cancer progression. Furthermore, we discuss the potential value of the chemokine system as a cancer prognostic marker. The chemokine system regulates the infiltration of immune cells into the tumor microenvironment, which induces both pro- and anti-immunity and promotes or suppresses tumor growth and proliferation, angiogenesis, and metastasis. Increasing evidence indicates the promising prognostic value of the chemokine system in cancer patients. While CCL2, CXCL10, and CX3CL1/CX3CR1 can serve as favorable or unfavorable prognostic factors depending on the cancer types, CCL14 and XCL1 possess good prognostic value. Other chemokines such as CXCL1, CXCL8, and CXCL12 are poor prognostic markers. Despite vast advances in our understanding of the complex nature of the chemokine system in tumor biology, knowledge about the multifaceted roles of the chemokine system in different types of cancers is still limited. Further studies are necessary to decipher distinct roles within the chemokine system in terms of cancer progression and to validate their potential value in cancer prognosis. Full article

(This article belongs to the Special Issue Chemokines and Chemokine Receptors: New Targets for Cancer Therapy)

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Other

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13 pages, 1753 KiB

Open AccessBrief Report

CXCL10 Is an Agonist of the CC Family Chemokine Scavenger Receptor ACKR2/D6

by Andy Chevigné, Bassam Janji, Max Meyrath, Nathan Reynders, Giulia D’Uonnolo, Tomasz Uchański, Malina Xiao, Guy Berchem, Markus Ollert, Yong-Jun Kwon, Muhammad Zaeem Noman and Martyna Szpakowska

Cancers 2021, 13(5), 1054; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051054 - 02 Mar 2021

Cited by 23 | Viewed by 4447

Abstract

Atypical chemokine receptors (ACKRs) are important regulators of chemokine functions. Among them, the atypical chemokine receptor ACKR2 (also known as D6) has long been considered as a scavenger of inflammatory chemokines exclusively from the CC family. In this study, by using highly sensitive β-arrestin recruitment assays based on NanoBiT and NanoBRET technologies, we identified the inflammatory CXC chemokine CXCL10 as a new strong agonist ligand for ACKR2. CXCL10 is known to play an important role in the infiltration of immune cells into the tumour bed and was previously reported to bind to CXCR3 only. We demonstrated that ACKR2 is able to internalize and reduce the availability of CXCL10 in the extracellular space. Moreover, we found that, in contrast to CC chemokines, CXCL10 activity towards ACKR2 was drastically reduced by the dipeptidyl peptidase 4 (DPP4 or CD26) N-terminal processing, pointing to a different receptor binding pocket occupancy by CC and CXC chemokines. Overall, our study sheds new light on the complexity of the chemokine network and the potential role of CXCL10 regulation by ACKR2 in many physiological and pathological processes, including tumour immunology. Our data also testify that systematic reassessment of chemokine-receptor pairing is critically needed as important interactions may remain unexplored. Full article

(This article belongs to the Special Issue Chemokines and Chemokine Receptors: New Targets for Cancer Therapy)

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