International Journal of Molecular Sciences

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15 pages, 4245 KiB

Open AccessArticle

CD9 Upregulation-Decreased CCL21 Secretion in Mesenchymal Stem Cells Reduces Cancer Cell Migration

by Chia-Chu Hsieh, Szu-Chun Hsu, Ming Yao and Dong-Ming Huang

Int. J. Mol. Sci. 2021, 22(4), 1738; https://doi.org/10.3390/ijms22041738 - 09 Feb 2021

Cited by 6 | Viewed by 3058

Abstract

Tetraspanin CD9 is widely expressed on various cell types, such as cancer cells and mesenchymal stem cells (MSCs), and/or cell-released exosomes. It has been reported that exosomal CD9 plays an important role in intercellular communications involved in cancer cell migration and metastasis. However, [...] Read more.

Tetraspanin CD9 is widely expressed on various cell types, such as cancer cells and mesenchymal stem cells (MSCs), and/or cell-released exosomes. It has been reported that exosomal CD9 plays an important role in intercellular communications involved in cancer cell migration and metastasis. However, reports on the effect of the CD9 of MSCs or MSC-derived exosomes on cancer cell migration are still lacking. In this study, using a transwell migration assay, we found that both dextran-coated iron oxide nanoparticles (dex-IO NPs) and ionomycin stimulated exosomal CD9 expression in human MSCs (hMSCs); however, hMSCs could not deliver them to melanoma cells to affect cell migration. Interestingly, a reduced migration of melanoma cell line was observed when the ionomycin-incubated hMSC-conditioned media but not dex-IO NP-labeled hMSC-conditioned media were in the bottom chamber. In addition, we found that dex-IO NPs decreased cellular CD9 expression in hMSCs but ionomycin increased this. Simultaneously, we found that ionomycin suppressed the expression and secretion of the chemokine CCL21 in hMSCs. The silencing of CD9 demonstrated an inhibitory role of cellular CD9 in CCL21 expression in hMSCs, suggesting that ionomycin could upregulate cellular CD9 to decrease CCL21 expression and secretion of hMSCs, which would reduce the migration of B16F10, A549 and U87MG cancer cell lines due to chemoattraction reduction of CCL21. The present study not only highlights the important role of bone marrow-derived hMSCs’ CD9-mediated CCL21 regulation in cancer bone metastasis but also suggests a new distinct pharmaceutical strategy for prevention or/and therapy of cancer metastasis. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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23 pages, 4265 KiB

Open AccessArticle

Investigation of the Impact from IL-2, IL-7, and IL-15 on the Growth and Signaling of Activated CD4⁺ T Cells

by Canaan Coppola, Brooks Hopkins, Steven Huhn, Zhimei Du, Zuyi Huang and William J. Kelly

Int. J. Mol. Sci. 2020, 21(21), 7814; https://doi.org/10.3390/ijms21217814 - 22 Oct 2020

Cited by 27 | Viewed by 5332

Abstract

While CAR-T therapy is a growing and promising area of cancer research, it is limited by high cost and the difficulty of consistently culturing T-cells to therapeutically relevant concentrations ex-vivo. Cytokines IL-2, IL-7 and IL-15 have been found to stimulate the growth of [...] Read more.

While CAR-T therapy is a growing and promising area of cancer research, it is limited by high cost and the difficulty of consistently culturing T-cells to therapeutically relevant concentrations ex-vivo. Cytokines IL-2, IL-7 and IL-15 have been found to stimulate the growth of T cells, however, the optimized combination of these three cytokines for T cell proliferation is unknown. In this study, we designed an integrated experimental and modeling approach to optimize cytokine supplementation for rapid expansion in clinical applications. We assessed the growth data for statistical improvements over no cytokine supplementation and used a systems biology approach to identify genes with the highest magnitude of expression change from control at several time points. Further, we developed a predictive mathematical model to project the growth rate for various cytokine combinations, and investigate genes and reactions regulated by cytokines in activated CD4⁺ T cells. The most favorable conditions from the T cell growth study and from the predictive model align to include the full range of IL-2 and IL-7 studied, and at lower levels of IL-15 (6 ng/mL or 36 ng/mL). The highest growth rates were observed where either IL-2 or IL-7 was at the highest concentration tested (15 ng/mL for IL-2 and 80 ng/mL for IL-7) while the other was at the lowest (1 ng/mL for IL-2 and 6 ng/mL for IL-7), or where both IL-2 and IL-7 concentrations are moderate-corresponding to condition keys 200, 020, and 110 respectively. This suggests a synergistic interaction of IL-2 and IL-7 with regards to promoting optimal proliferation and survival of the activated CD4⁺ T cells. Transcriptomic data analysis identified the genes and transcriptional regulators up/down-regulated by each of the cytokines IL-2, IL-7, and IL-15. It was found that the genes with persistent expressing changes were associated with major pathways involved in cell growth and proliferation. In addition to influencing T cell metabolism, the three cytokines were found to regulate specific genes involved in TCR, JAK/STAT, MAPK, AKT and PI3K-AKT signaling. The developed Fuzzy model that can predict the growth rate of activated CD4⁺ T cells for various combinations of cytokines, along with identified optimal cytokine cocktails and important genes found in transcriptomic data, can pave the way for optimizing activated CD4 T cells by regulating cytokines in the clinical setting. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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11 pages, 2298 KiB

Open AccessArticle

High Expression of Cannabinoid Receptor 2 on Cytokine-Induced Killer Cells and Multiple Myeloma Cells

by Francesca Garofano and Ingo G. H. Schmidt-Wolf

Int. J. Mol. Sci. 2020, 21(11), 3800; https://doi.org/10.3390/ijms21113800 - 27 May 2020

Cited by 9 | Viewed by 4225

Abstract

Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized. Cannabidiol (CBD) may be used [...] Read more.

Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized. Cannabidiol (CBD) may be used to treat various diseases. CBD is known to exert immunomodulatory effects through the activation of cannabinoid receptor 2 (CB2), which is expressed in high levels in the hematopoietic system. Cytokine-induced killer (CIK) cells are a heterogeneous population of polyclonal T lymphocytes obtained via ex vivo sequential incubation of peripheral blood mononuclear cells (PBMCs) with interferon-γ (IFN-γ), anti CD3 monoclonal antibody, and IL-2. They are characterized by the expression of CD3+ and CD56+, which are surface markers common to T lymphocytes and natural killer (NK) cells. CIK cells are mainly used in hematological patients who suffer relapse after allogeneic transplantation. Here, we investigated their antitumor effect in combination with pure cannabidiol in KMS-12 MM cells by lactate dehydrogenase LDH cytotoxicity assay, CCK-8 assay, and flow cytometry analysis. The surface and intracellular CB2 expressions on CIK cells and on KMS-12 and U-266 MM cell lines were also detected by flow cytometry. Our findings confirm that the CB2 receptor is highly expressed on CIK cells as well as on MM cells. CBD was able to decrease the viability of tumor cells and can have a protective role for CIK cells. It also inhibits the cytotoxic activity of CIKs against MM at high concentrations, so in view of a clinical perspective, it has to be considered that the lower concentration of 1 µM can be used in combination with CIK cells. Further studies will be required to address the mechanism of CBD modulation of CIK cells in more detail. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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18 pages, 3372 KiB

Open AccessArticle

Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6

by Mohd Yousuf, Anas Shamsi, Parvez Khan, Mohd Shahbaaz, Mohamed F. AlAjmi, Afzal Hussain, Gulam Mustafa Hassan, Asimul Islam, Qazi Mohd Rizwanul Haque and Md. Imtaiyaz Hassan

Int. J. Mol. Sci. 2020, 21(10), 3526; https://doi.org/10.3390/ijms21103526 - 15 May 2020

Cited by 73 | Viewed by 4987

Abstract

Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic [...] Read more.

Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of K = 10⁷ M⁻¹ and subsequently inhibits its enzyme activity with an IC₅₀ value of 3.053 µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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Review

Jump to: Research

23 pages, 1908 KiB

Open AccessReview

Chemokine-Cytokine Networks in the Head and Neck Tumor Microenvironment

by Sabah Nisar, Parvaiz Yousuf, Tariq Masoodi, Nissar A. Wani, Sheema Hashem, Mayank Singh, Geetanjali Sageena, Deepika Mishra, Rakesh Kumar, Mohammad Haris, Ajaz A. Bhat and Muzafar A. Macha

Int. J. Mol. Sci. 2021, 22(9), 4584; https://doi.org/10.3390/ijms22094584 - 27 Apr 2021

Cited by 31 | Viewed by 5182

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations [...] Read more.

Head and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations in the cellular and non-cellular components of the HNSCC tumor micro-environment (TME) play a critical role in regulating many hallmarks of cancer development including evasion of apoptosis, activation of invasion, metastasis, angiogenesis, response to therapy, immune escape mechanisms, deregulation of energetics, and therefore the development of an overall aggressive HNSCC phenotype. Cytokines and chemokines are small secretory proteins produced by neoplastic or stromal cells, controlling complex and dynamic cell–cell interactions in the TME to regulate many cancer hallmarks. This review summarizes the current understanding of the complex cytokine/chemokine networks in the HNSCC TME, their role in activating diverse signaling pathways and promoting tumor progression, metastasis, and therapeutic resistance development. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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15 pages, 2325 KiB

Open AccessReview

Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer

by Jingwei Shi, Xujun Song, Benno Traub, Michael Luxenhofer and Marko Kornmann

Int. J. Mol. Sci. 2021, 22(6), 2998; https://doi.org/10.3390/ijms22062998 - 15 Mar 2021

Cited by 37 | Viewed by 5296

Abstract

Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally [...] Read more.

Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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17 pages, 325 KiB

Open AccessReview

Is the C-C Motif Ligand 2–C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis?

by Hiroaki Iwamoto, Kouji Izumi and Atsushi Mizokami

Int. J. Mol. Sci. 2020, 21(23), 9328; https://doi.org/10.3390/ijms21239328 - 07 Dec 2020

Cited by 27 | Viewed by 3106

Abstract

C-C motif ligand 2 (CCL2) was originally reported as a chemical mediator attracting mononuclear cells to inflammatory tissue. Many studies have reported that CCL2 can directly activate cancer cells through a variety of mechanisms. CCL2 can also promote cancer progression indirectly through increasing [...] Read more.

C-C motif ligand 2 (CCL2) was originally reported as a chemical mediator attracting mononuclear cells to inflammatory tissue. Many studies have reported that CCL2 can directly activate cancer cells through a variety of mechanisms. CCL2 can also promote cancer progression indirectly through increasing the recruitment of tumor-associated macrophages into the tumor microenvironment. The role of CCL2 in cancer progression has gradually been understood, and various preclinical cancer models elucidate that CCL2 and its receptor C-C chemokine receptor 2 (CCR2) are attractive targets for intervention in cancer development. However, clinically available drugs that regulate the CCL2–CCR2 axis as anticancer agents are not available at this time. The complete elucidation of not only the oncological but also the physiological functions of the CCL2–CCR2 axis is required for achieving a satisfactory effect of the CCL2–CCR2 axis-targeted therapy. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

11 pages, 433 KiB

Open AccessReview

The Role of Chemokine Receptor CXCR3 and Its Ligands in Renal Cell Carcinoma

by Monika Gudowska-Sawczuk, Jacek Kudelski and Barbara Mroczko

Int. J. Mol. Sci. 2020, 21(22), 8582; https://doi.org/10.3390/ijms21228582 - 14 Nov 2020

Cited by 20 | Viewed by 2168

Abstract

The major invasive subtype of kidney cancer is renal cell carcinoma (RCC). The essential components of cancer development are chronic inflammation and neoangiogenesis. It has been suggested that the chemokine ligand 9, -10, –11 (CXCL9–11) and chemokine receptor 3 (CXCR3) chemokines receptor expressed [...] Read more.

The major invasive subtype of kidney cancer is renal cell carcinoma (RCC). The essential components of cancer development are chronic inflammation and neoangiogenesis. It has been suggested that the chemokine ligand 9, -10, –11 (CXCL9–11) and chemokine receptor 3 (CXCR3) chemokines receptor expressed on monocytes, T and NK cells may be involved in the inhibition of angiogenesis. However, to date, little is known about the potential clinical significance of these chemokines and their receptor in renal cell carcinoma. Therefore, in this review, we described the role of CXCR3 and its ligands in pathogenesis of RCC. We performed an extensive search of the current literature in our investigation, using the MEDLINE/PubMed database. The changes of chemokines and their specific receptor in renal cell carcinoma were observed. Published studies revealed an increased expression of CXCR3 and elevated concentration of its ligands in RCC. The association between treatment of RCC and CXCL9–11/CXCR3 concentration and expression was also observed. Moreover, CXCR3 and its ligands levels were related to patient’s prognosis, risk of metastasis and tumor growth. This review describes the potential role of CXCR3 and its ligands in pathogenesis of RCC, as well as their potential immune-therapeutic significance. However, future studies should aim to confirm the clinical and prognostic role of CXCL9–11/CXCR3 in renal cell carcinoma. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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22 pages, 1715 KiB

Open AccessReview

MicroRNAs: As Critical Regulators of Tumor- Associated Macrophages

by Bilash Chatterjee, Priyanka Saha, Subhankar Bose, Devendra Shukla, Nabanita Chatterjee, Sanjay Kumar, Prem Prakash Tripathi and Amit Kumar Srivastava

Int. J. Mol. Sci. 2020, 21(19), 7117; https://doi.org/10.3390/ijms21197117 - 27 Sep 2020

Cited by 16 | Viewed by 4202

Abstract

Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs [...] Read more.

Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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13 pages, 503 KiB

Open AccessReview

In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update

by Thangavelu Soundara Rajan, Agnese Gugliandolo, Placido Bramanti and Emanuela Mazzon

Int. J. Mol. Sci. 2020, 21(18), 6514; https://doi.org/10.3390/ijms21186514 - 06 Sep 2020

Cited by 33 | Viewed by 6426

Abstract

Adoptive T cell immunotherapy has received considerable interest in the treatment of cancer. In recent years, chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising therapy in cancer treatment. In CAR T therapy, T cells from the patients are [...] Read more.

Adoptive T cell immunotherapy has received considerable interest in the treatment of cancer. In recent years, chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising therapy in cancer treatment. In CAR T therapy, T cells from the patients are collected, reprogrammed genetically against tumor antigens, and reintroduced into the patients to trigger an immense immune response against cancer cells. CAR T therapy is successful in hematologic malignancies; however, in solid tumors, CAR T therapy faces multiple challenges, including the on-target off-tumor phenomenon, as most of the tumor-associated antigens are expressed in normal cells as well. Consequently, a transient in vitro-transcribed anti-mRNA-based CAR T cell (IVT mRNA CAR T) approach has been investigated to produce controlled cytotoxicity for a limited duration to avoid any undesirable effects in patients. In vitro and in vivo studies demonstrated the therapeutic ability of mRNA-engineered T cells in solid tumors, including melanoma, neuroblastoma and ovarian cancer; however, very few clinical trials are registered. In the present review, we discuss the effect of IVT mRNA CAR T therapy in preclinical studies related to hematologic malignancies and solid tumor management. In addition, we discuss the clinical trial studies based on IVT mRNA CAR T therapy in cancer. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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18 pages, 1506 KiB

Open AccessReview

Molecular and Cellular Factors Associated with Racial Disparity in Breast Cancer

by Manish Charan, Ajeet K. Verma, Shahid Hussain, Swati Misri, Sanjay Mishra, Sarmila Majumder, Bhuvaneswari Ramaswamy, Dinesh Ahirwar and Ramesh K. Ganju

Int. J. Mol. Sci. 2020, 21(16), 5936; https://doi.org/10.3390/ijms21165936 - 18 Aug 2020

Cited by 13 | Viewed by 4345

Abstract

Recent studies have demonstrated that racial differences can influence breast cancer incidence and survival rate. African American (AA) women are at two to three fold higher risk for breast cancer than other ethnic groups. AA women with aggressive breast cancers show worse prognoses [...] Read more.

Recent studies have demonstrated that racial differences can influence breast cancer incidence and survival rate. African American (AA) women are at two to three fold higher risk for breast cancer than other ethnic groups. AA women with aggressive breast cancers show worse prognoses and higher mortality rates relative to Caucasian (CA) women. Over the last few years, effective treatment strategies have reduced mortality from breast cancer. Unfortunately, the breast cancer mortality rate among AA women remains higher compared to their CA counterparts. The focus of this review is to underscore the racial differences and differential regulation/expression of genetic signatures in CA and AA women with breast cancer. Moreover, immune cell infiltration significantly affects the clinical outcome of breast cancer. Here, we have reviewed recent findings on immune cell recruitment in the tumor microenvironment (TME) and documented its association with breast cancer racial disparity. In addition, we have extensively discussed the role of cytokines, chemokines, and other cell signaling molecules among AA and CA breast cancer patients. Furthermore, we have also reviewed the distinct genetic and epigenetic changes in AA and CA patients. Overall, this review article encompasses various molecular and cellular factors associated with breast cancer disparity that affects mortality and clinical outcome. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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18 pages, 639 KiB

Open AccessReview

The CCL20-CCR6 Axis in Cancer Progression

by Suguru Kadomoto, Kouji Izumi and Atsushi Mizokami

Int. J. Mol. Sci. 2020, 21(15), 5186; https://doi.org/10.3390/ijms21155186 - 22 Jul 2020

Cited by 116 | Viewed by 11300

Abstract

Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein [...] Read more.

Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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24 pages, 1253 KiB

Open AccessReview

Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma

by Sabah Akhtar, Tayyiba A. Ali, Ammara Faiyaz, Omar S. Khan, Syed Shadab Raza, Michal Kulinski, Halima El Omri, Ajaz A. Bhat and Shahab Uddin

Int. J. Mol. Sci. 2020, 21(14), 5002; https://doi.org/10.3390/ijms21145002 - 15 Jul 2020

Cited by 19 | Viewed by 3731

Abstract

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host’s immune system and microenvironment are of [...] Read more.

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host’s immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κβ, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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29 pages, 785 KiB

Open AccessReview

Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis

by Timothy O. Adekoya and Ricardo M. Richardson

Int. J. Mol. Sci. 2020, 21(12), 4449; https://doi.org/10.3390/ijms21124449 - 23 Jun 2020

Cited by 97 | Viewed by 9647

Abstract

The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, [...] Read more.

The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, along with their receptors and signaling axis, constitute important factors that help drive the sequence of events that lead to metastasis of prostate cancer. These proteins are involved in extracellular matrix remodeling, epithelial-mesenchymal-transition, angiogenesis, tumor invasion, premetastatic niche creation, extravasation, re-establishment of tumor cells in secondary organs as well as the remodeling of the metastatic tumor microenvironment. This review presents an overview of the main cytokines/chemokines, including IL-6, CXCL12, TGFβ, CXCL8, VEGF, RANKL, CCL2, CX3CL1, IL-1, IL-7, CXCL1, and CXCL16, that exert modulatory roles in prostate cancer metastasis. We also provide extensive description of their aberrant expression patterns in both advanced disease states and metastatic sites, as well as their functional involvement in the various stages of the prostate cancer metastatic process. Full article

(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)

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