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The Significance of Chemokines for Cancer Processes
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The Significance of Chemokines for Cancer Processes

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 76669

Special Issue Editor

Dr. Irena Baranowska-Bosiacka

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Guest Editor
Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Szczecin, Poland
Interests: metallomics; neurotoxicology; neurobiochemistry and molecular biology of heavy metals

Special Issue Information

Dear Colleagues,

Chemokines are a group of over 50 chemotactic cytokines divided into 4 subgroups according to differences in the conservative motif at the N-terminus. They play an important role in regulating the chemotaxis of immune cells and in neoplastic processes. Thanks to a better understanding of the molecular mechanisms of cancer, we now know that chemokines are important not only in the migration and metastasis of cancer cells but also in the recruitment of non-cancer cells to the tumor niche, in angiogenesis, and in autocrine stimulation of cancer cell proliferation. A thorough understanding of the mechanisms of chemokine action in neoplastic processes would allow us not only to understand the functioning of a tumor, but also to develop effective therapeutic approaches for the treatment of cancers.

This is the reason why we have decided to create a Special Issue of our journal. We would like to encourage authors to send their original papers and reviews about the role of chemokines in neoplastic processes. In particular:

  • The importance of a given chemokine in migration and metastasis of cancer cells.
  • The importance of a given chemokine in recruiting non-cancer cells into a cancer niche.
  • The role of a given chemokine in tumor angiogenesis.
  • In vivo tests on new drugs, whose mechanism of action consists in interfering with a given chemokine or chemokine receptor.

Dr. Irena Baranowska-Bosiacka
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (7 papers)

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Research

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20 pages, 6043 KiB  
Article
Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells
by Ha Thi Thu Do and Jungsook Cho
Int. J. Mol. Sci. 2021, 22(1), 89; https://doi.org/10.3390/ijms22010089 - 23 Dec 2020
Cited by 21 | Viewed by 4036
Abstract
Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the [...] Read more.
Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis. Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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Review

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25 pages, 3248 KiB  
Review
Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy
by Pedro Bule, Sandra Isabel Aguiar, Frederico Aires-Da-Silva and Joana Nunes Ribeiro Dias
Int. J. Mol. Sci. 2021, 22(18), 9804; https://doi.org/10.3390/ijms22189804 - 10 Sep 2021
Cited by 109 | Viewed by 9744
Abstract
Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. [...] Read more.
Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options. Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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15 pages, 1247 KiB  
Review
Roles of CCL2-CCR2 Axis in the Tumor Microenvironment
by Suguru Kadomoto, Kouji Izumi and Atsushi Mizokami
Int. J. Mol. Sci. 2021, 22(16), 8530; https://doi.org/10.3390/ijms22168530 - 8 Aug 2021
Cited by 75 | Viewed by 8286
Abstract
Chemokines are a small family of cytokines that were first discovered as chemotactic factors in leukocytes during inflammation, and reports on the relationship between chemokines and cancer progression have recently been increasing. The CCL2-CCR2 axis is one of the major chemokine signaling pathways, [...] Read more.
Chemokines are a small family of cytokines that were first discovered as chemotactic factors in leukocytes during inflammation, and reports on the relationship between chemokines and cancer progression have recently been increasing. The CCL2-CCR2 axis is one of the major chemokine signaling pathways, and has various functions in tumor progression, such as increasing tumor cell proliferation and invasiveness, and creating a tumor microenvironment through increased angiogenesis and recruitment of immunosuppressive cells. This review discusses the roles of the CCL2-CCR2 axis and the tumor microenvironment in cancer progression and their future roles in cancer therapy. Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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29 pages, 1373 KiB  
Review
CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4
by Jan Korbecki, Klaudyna Kojder, Donata Simińska, Romuald Bohatyrewicz, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2020, 21(21), 8412; https://doi.org/10.3390/ijms21218412 - 9 Nov 2020
Cited by 240 | Viewed by 18766
Abstract
CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all [...] Read more.
CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL). Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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25 pages, 2092 KiB  
Review
CCL18 in the Progression of Cancer
by Jan Korbecki, Mateusz Olbromski and Piotr Dzięgiel
Int. J. Mol. Sci. 2020, 21(21), 7955; https://doi.org/10.3390/ijms21217955 - 26 Oct 2020
Cited by 56 | Viewed by 7264
Abstract
A neoplastic tumor consists of cancer cells that interact with each other and non-cancerous cells that support the development of the cancer. One such cell are tumor-associated macrophages (TAMs). These cells secrete many chemokines into the tumor microenvironment, including especially a large amount [...] Read more.
A neoplastic tumor consists of cancer cells that interact with each other and non-cancerous cells that support the development of the cancer. One such cell are tumor-associated macrophages (TAMs). These cells secrete many chemokines into the tumor microenvironment, including especially a large amount of CCL18. This chemokine is a marker of the M2 macrophage subset; this is the reason why an increase in the production of CCL18 is associated with the immunosuppressive nature of the tumor microenvironment and an important element of cancer immune evasion. Consequently, elevated levels of CCL18 in the serum and the tumor are connected with a worse prognosis for the patient. This paper shows the importance of CCL18 in neoplastic processes. It includes a description of the signal transduction from PITPNM3 in CCL18-dependent migration, invasion, and epithelial-to-mesenchymal transition (EMT) cancer cells. The importance of CCL18 in angiogenesis has also been described. The paper also describes the effect of CCL18 on the recruitment to the cancer niche and the functioning of cells such as TAMs, regulatory T cells (Treg), cancer-associated fibroblasts (CAFs) and tumor-associated dendritic cells (TADCs). The last part of the paper describes the possibility of using CCL18 as a therapeutic target during anti-cancer therapy. Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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34 pages, 3029 KiB  
Review
CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands
by Jan Korbecki, Szymon Grochans, Izabela Gutowska, Katarzyna Barczak and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2020, 21(20), 7619; https://doi.org/10.3390/ijms21207619 - 15 Oct 2020
Cited by 215 | Viewed by 19020
Abstract
CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In [...] Read more.
CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (Treg). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis. Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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Graphical abstract

32 pages, 2514 KiB  
Review
Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review
by Jan Korbecki, Klaudyna Kojder, Katarzyna Barczak, Donata Simińska, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2020, 21(16), 5647; https://doi.org/10.3390/ijms21165647 - 6 Aug 2020
Cited by 57 | Viewed by 8843
Abstract
Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we [...] Read more.
Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche. Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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