The Distinct Roles of CXCR3 Variants and Their Ligands in the Tumor Microenvironment

First thought to orchestrate exclusively leukocyte trafficking, chemokines are now acknowledged for their multiple roles in the regulation of cell proliferation, differentiation, and survival. Dysregulation of their normal functions contributes to various pathologies, including inflammatory diseases and cancer. The two chemokine receptor 3 variants CXCR3-A and CXCR3-B, together with their cognate chemokines (CXCL11, CXCL10, CXCL9, CXCL4, and CXCL4L1), are involved in the control but also in the development of many tumors. CXCR3-A drives the infiltration of leukocytes to the tumor bed to modulate tumor progression (paracrine axis). Conversely, tumor-driven changes in the expression of the CXCR3 variants and their ligands promote cancer progression (autocrine axis). This review summarizes the anti- and pro-tumoral activities of the CXCR3 variants and their associated chemokines with a focus on the understanding of their distinct biological roles in the tumor microenvironment.

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The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment

AJP Cell Physiology ◽

10.1152/ajpcell.00378.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. C542-C554 ◽

Cited By ~ 3

Author(s):

Andreas Bikfalvi ◽

Clotilde Billottet

Keyword(s):

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Tumor Cells ◽

Tumor Immunity ◽

Chemokine Receptor ◽

Immune Cells ◽

Immune Dysfunction ◽

Mechanisms Of Action ◽

Migration Of Cells

Chemokines are a family of soluble cytokines that act as chemoattractants to guide the migration of cells, in particular of immune cells. However, chemokines are also involved in cell proliferation, differentiation, and survival. Chemokines are associated with a variety of human diseases including chronic inflammation, immune dysfunction, cancer, and metastasis. This review discusses the expression of CC and CXC chemokines in the tumor microenvironment and their supportive and inhibitory roles in tumor progression, angiogenesis, metastasis, and tumor immunity. We also specially focus on the diverse roles of CXC chemokines (CXCL9–11, CXCL4 and its variant CXCL4L1) and their two chemokine receptor CXCR3 isoforms, CXCR3-A and CXCR3-B. These two distinct isoforms have divergent roles in tumors, either promoting (CXCR3-A) or inhibiting (CXCR3-B) tumor progression. Their effects are mediated not only directly in tumor cells but also indirectly via the regulation of angiogenesis and tumor immunity. A full comprehension of their mechanisms of action is critical to further validate these chemokines and their receptors as biomarkers or therapeutic targets in cancer.

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Hypoxia and the Tumor Microenvironment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211036304 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110363

Author(s):

Yue Li ◽

Long Zhao ◽

Xiao-Feng Li

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Poor Prognosis ◽

Tumor Biology ◽

Metastatic Potential ◽

Tumor Detection ◽

Tumor Aggressiveness

Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

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The Extracellular Matrix and Vesicles Modulate the Breast Tumor Microenvironment

Bioengineering ◽

10.3390/bioengineering7040124 ◽

2020 ◽

Vol 7 (4) ◽

pp. 124 ◽

Cited By ~ 1

Author(s):

Jun Yang ◽

Gokhan Bahcecioglu ◽

Pinar Zorlutuna

Keyword(s):

Breast Cancer ◽

Extracellular Matrix ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Signaling Molecules ◽

Clinical Applications ◽

Breast Cancer Progression ◽

Multiple Roles ◽

Biophysical Properties ◽

The Impact

Emerging evidence has shown multiple roles of the tumor microenvironment (TME) components, specifically the extracellular matrix (ECM), in breast cancer development, progression, and metastasis. Aside from the biophysical properties and biochemical composition of the breast ECM, the signaling molecules are extremely important in maintaining homeostasis, and in the breast TME, they serve as the key components that facilitate tumor progression and immune evasion. Extracellular vesicles (EVs), the mediators that convey messages between the cells and their microenvironment through signaling molecules, have just started to capture attention in breast cancer research. In this comprehensive review, we first provide an overview of the impact of ECM in breast cancer progression as well as the alterations occurring in the TME during this process. The critical importance of EVs and their biomolecular contents in breast cancer progression and metastasis are also discussed. Finally, we discuss the potential biomedical or clinical applications of these extracellular components, as well as how they impact treatment outcomes.

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MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2020.607891 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lucia Suarez-Lopez ◽

Yi Wen Kong ◽

Ganapathy Sriram ◽

Jesse C. Patterson ◽

Samantha Rosenberg ◽

...

Keyword(s):

Colon Cancer ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Chronic Inflammation ◽

Cancer Progression ◽

Tumor Angiogenesis ◽

Cell Types ◽

Adoptive Cell Transfer ◽

Tumor Associated Macrophages

Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.

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NKG2D signaling regulates IL-17A-producing γδT cells to promote cancer progression

10.1101/2021.08.26.457761 ◽

2021 ◽

Author(s):

Sophie Curio ◽

Sarah C Edwards ◽

Toshiyasu Suzuki ◽

Jenny McGovern ◽

Chiara Triulzi ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Progression ◽

Cell Activation ◽

Tumor Development ◽

Cell Receptor ◽

Dependent Manner ◽

Γδt Cells ◽

Γδt Cell

γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance and homeostasis. γδT cell activation is mediated by the T cell receptor composed of γ and δ chains, as well as activating receptors for stress-induced ligands, such as NKG2D. Contrary to the well-established anti-tumor function of γδT cells, recent studies have shown that γδT cells can promote tumor development in certain contexts. However, the mechanisms leading to this disease-promoting role remain poorly understood. Here, we show that mice lacking γδT cells survive longer in a mouse model of intestinal cancer, further supporting their pro-tumoral role. In a surprising conceptual twist, we found that these pro-tumor γδT cells are regulated by NKG2D signaling, a receptor normally associated with cancer cell killing. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduces the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increases the frequency of γδT cells. Together, these data support the hypothesis that in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.

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

Cancers ◽

10.3390/cancers12041036 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1036 ◽

Cited By ~ 2

Author(s):

Balsam Rizeq ◽

Mohammed Imad Malki

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Cancer Metastasis ◽

Cellular Proliferation ◽

Inflammatory Diseases ◽

Breast Cancer Metastasis ◽

Breast Cancer Progression ◽

Cellular Interactions

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.

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Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer

Cancers ◽

10.3390/cancers13112584 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2584

Author(s):

Colin Timaxian ◽

Christoph F. A. Vogel ◽

Charlotte Orcel ◽

Diana Vetter ◽

Camille Durochat ◽

...

Keyword(s):

Breast Cancer ◽

Reactive Oxygen Species ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Chemokine Receptor ◽

Primary Tumor ◽

Ros Production ◽

Oxygen Species ◽

Chemokine Receptor Cxcr2 ◽

Tumor Associated Neutrophils

Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2−/− TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects.

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Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

Nutrients ◽

10.3390/nu14010079 ◽

2021 ◽

Vol 14 (1) ◽

pp. 79

Author(s):

Getinet M. Adinew ◽

Equar Taka ◽

Bereket Mochona ◽

Ramesh B Badisa ◽

Elizabeth A Mazzio ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Potential ◽

Advanced Tumor ◽

Uncontrolled Cell Proliferation

To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.

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The Inflammatory Chemokine CCL5 and Cancer Progression

Mediators of Inflammation ◽

10.1155/2014/292376 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 166

Author(s):

Donatella Aldinucci ◽

Alfonso Colombatti

Keyword(s):

Cell Proliferation ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Hematological Malignancies ◽

Therapeutic Strategies ◽

Cancer Cell Proliferation ◽

Inflammatory Chemokines ◽

Immunosuppressive Microenvironment ◽

Receptor Ccr5

Until recently, inflammatory chemokines were viewed mainly as indispensable “gate keepers” of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion.

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CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker

Cancers ◽

10.3390/cancers11111803 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1803 ◽

Cited By ~ 9

Author(s):

Alexandra Landras ◽

Coralie Reger de Moura ◽

Fanelie Jouenne ◽

Celeste Lebbe ◽

Suzanne Menashi ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Progression ◽

Cancer Diagnosis ◽

Tumor Development ◽

Strategy Development ◽

Tumor Biomarker ◽

Diagnosis And Prognosis ◽

Promising Target ◽

Cd147 Expression

Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 is a glycoprotein involved in the regulation of the tumor microenvironment and cancer progression by several mechanisms—in particular, by the control of glycolysis and also by its well-known ability to induce proteinases leading to matrix degradation, tumor cell invasion, metastasis and angiogenesis. Accumulating evidence has demonstrated the role of CD147 expression in tumor progression and prognosis, suggesting it as a relevant tumor biomarker for cancer diagnosis and prognosis, as well as validating its potential as a promising therapeutic target in cancers.

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