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Tumor Microenvironment: Interaction and Metabolism
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Tumor Microenvironment: Interaction and Metabolism

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: closed (15 April 2019) | Viewed by 115237

Special Issue Editor

Dr. Bassam Janji

E-Mail Website
Guest Editor
Tumor Immunotherapy and Microenvironment (TIME) group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City L-1526, Luxembourg
Interests: tumor microenvironment; hypoxia; tumor immune response; natural killer; cytotoxic T lymphocytes; autophagy; cancer immunotherapy; immune checkpoint blockades; tumor immune landscape
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Cancer progression is now considered to be largely influenced by the tumor microenvironment, which is not only composed of proliferating cancer cells but also of stromal cells, blood vessels and endothelial cells, infiltrating immune cells, and a variety of associated tissue cells. In addition, factors in the tumor microenvironment, including hypoxia, play a key role in cancer progression, metastasis, and resistance to therapies. Therefore, tumor cells rewire their metabolic properties to shape hypoxic stress, resist anti-cancer therapies, and escape the immune system. Such cancer cell adaptations can be executed autonomously or through interactions with other cells in the tumor microenvironment. In this regard, it has become clear that anti-cancer therapies can be more effective by combining with agents that target key factors in the tumor microenvironment in order to suppress resistance mechanisms associated with the complexity of the tumor microenvironment. Elaborating such combination therapies remains very challenging, since it relies on better knowledge of the interaction between cancer cells and their tumor microenvironment.  The aim of this Special Issue is to provide a comprehensive review covering the most recent developments in our understanding of the impact of the tumor microenvironment on tumor development and metabolic adaptation. By focusing on the most effective current therapeutic strategies to target pathways, molecules, metabolites, and components in the tumor microenvironment, the goal of this issue is to provide an overview on strategies that can be considered to overcome a hostile tumor microenvironment and elaborate a more favourable tumor microenvironment to support anti-cancer therapies.

Dr. Bassam Janji
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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.

Keywords

  • hypoxia
  • tumor microenvironment
  • stromal cells
  • immune cells
  • immunotherapy
  • metabolic switch
  • tumor cell plasticity
  • autophagy
  • tumor vasculature

Published Papers (15 papers)

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Research

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22 pages, 5518 KiB  
Article
Diverse Roads Taken by 13C-Glucose-Derived Metabolites in Breast Cancer Cells Exposed to Limiting Glucose and Glutamine Conditions
by Maria Gkiouli, Philipp Biechl, Wolfgang Eisenreich and Angela M. Otto
Cells 2019, 8(10), 1113; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101113 - 20 Sep 2019
Cited by 16 | Viewed by 6351
Abstract
In cancers, tumor cells are exposed to fluctuating nutrient microenvironments with limiting supplies of glucose and glutamine. While the metabolic program has been related to the expression of oncogenes, only fractional information is available on how variable precarious nutrient concentrations modulate the cellular [...] Read more.
In cancers, tumor cells are exposed to fluctuating nutrient microenvironments with limiting supplies of glucose and glutamine. While the metabolic program has been related to the expression of oncogenes, only fractional information is available on how variable precarious nutrient concentrations modulate the cellular levels of metabolites and their metabolic pathways. We thus sought to obtain an overview of the metabolic routes taken by 13C-glucose-derived metabolites in breast cancer MCF-7 cells growing in combinations of limiting glucose and glutamine concentrations. Isotopologue profiles of key metabolites were obtained by gas chromatography/mass spectrometry (GC/MS). They revealed that in limiting and standard saturating medium conditions, the same metabolic routes were engaged, including glycolysis, gluconeogenesis, as well as the TCA cycle with glutamine and pyruvate anaplerosis. However, the cellular levels of 13C-metabolites, for example, serine, alanine, glutamate, malate, and aspartate, were highly sensitive to the available concentrations and the ratios of glucose and glutamine. Notably, intracellular lactate concentrations did not reflect the Warburg effect. Also, isotopologue profiles of 13C-serine as well as 13C-alanine show that the same glucose-derived metabolites are involved in gluconeogenesis and pyruvate replenishment. Thus, anaplerosis and the bidirectional flow of central metabolic pathways ensure metabolic plasticity for adjusting to precarious nutrient conditions. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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14 pages, 3948 KiB  
Article
Nodal Facilitates Differentiation of Fibroblasts to Cancer-Associated Fibroblasts that Support Tumor Growth in Melanoma and Colorectal Cancer
by Ziqian Li, Junjie Zhang, Jiawang Zhou, Linlin Lu, Hongsheng Wang, Ge Zhang, Guohui Wan, Shaohui Cai and Jun Du
Cells 2019, 8(6), 538; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060538 - 04 Jun 2019
Cited by 29 | Viewed by 4839
Abstract
Fibroblasts become cancer-associated fibroblasts (CAFs) in the tumor microenvironment after activation by transforming growth factor-β (TGF-β) and are critically involved in cancer progression. However, it is unknown whether the TGF superfamily member Nodal, which is expressed in various tumors but not expressed in [...] Read more.
Fibroblasts become cancer-associated fibroblasts (CAFs) in the tumor microenvironment after activation by transforming growth factor-β (TGF-β) and are critically involved in cancer progression. However, it is unknown whether the TGF superfamily member Nodal, which is expressed in various tumors but not expressed in normal adult tissue, influences the fibroblast to CAF conversion. Here, we report that Nodal has a positive correlation with α-smooth muscle actin (α-SMA) in clinical melanoma and colorectal cancer (CRC) tissues. We show the Nodal converts normal fibroblasts to CAFs, together with Snail and TGF-β signaling pathway activation in fibroblasts. Activated CAFs promote cancer growth in vitro and tumor-bearing mouse models in vivo. These results demonstrate that intercellular crosstalk between cancer cells and fibroblasts is mediated by Nodal, which controls tumor growth, providing potential targets for the prevention and treatment of tumors. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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12 pages, 4118 KiB  
Article
Prognostic Significance of Serum Free Amino Acids in Head and Neck Cancers
by Vit Vsiansky, Marketa Svobodova, Jaromir Gumulec, Natalia Cernei, Dagmar Sterbova, Ondrej Zitka, Rom Kostrica, Pavel Smilek, Jan Plzak, Jan Betka, David Kalfert, Michal Masarik and Martina Raudenska
Cells 2019, 8(5), 428; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050428 - 09 May 2019
Cited by 14 | Viewed by 5915
Abstract
Despite distinctive advances in the field of head and neck squamous cell cancer (HNSCC) biomarker discovery, the spectrum of clinically useful prognostic serum biomarkers is limited. As metabolic activities in highly proliferative transformed cells are fundamentally different from those in non-transformed cells, specific [...] Read more.
Despite distinctive advances in the field of head and neck squamous cell cancer (HNSCC) biomarker discovery, the spectrum of clinically useful prognostic serum biomarkers is limited. As metabolic activities in highly proliferative transformed cells are fundamentally different from those in non-transformed cells, specific shifts in concentration of different metabolites may serve as diagnostic or prognostic markers. Blood amino acids have been identified as promising biomarkers in different cancers before, but little is known about this field in HNSCC. Blood amino acid profiles of 140 HNSCC patients were examined using high-performance liquid chromatography. Cox proportional hazards regression model was used to assess the prognostic value of amino acid concentrations in serum. Colony forming assay was used to identify the effect of amino acids that were significant in Cox proportional hazards regression models on colony forming ability of FaDu and Detroit 562 cell lines. In the multivariable Cox regression model for overall survival (OS), palliative treatment was associated with an unfavourable prognosis while high serum levels of methionine have had a positive prognostic impact. In the relapse-free survival (RFS) multivariable model, methionine was similarly identified as a positive prognostic factor, along with tumor localization in the oropharynx. Oral cavity localization and primary radio(chemo)therapy treatment strategy have been linked to poorer RFS. 1mM serine was shown to support the forming of colonies in both tested HNSCC cell lines. Effect of methionine was exactly the opposite. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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20 pages, 4859 KiB  
Article
CD44s Assembles Hyaluronan Coat on Filopodia and Extracellular Vesicles and Induces Tumorigenicity of MKN74 Gastric Carcinoma Cells
by Kai Härkönen, Sanna Oikari, Heikki Kyykallio, Janne Capra, Sini Hakkola, Kirsi Ketola, Uma Thanigai Arasu, George Daaboul, Andrew Malloy, Carla Oliveira, Otto Jokelainen, Reijo Sironen, Jaana M. Hartikainen and Kirsi Rilla
Cells 2019, 8(3), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8030276 - 22 Mar 2019
Cited by 26 | Viewed by 5685
Abstract
CD44 is a multifunctional adhesion molecule typically upregulated in malignant, inflamed and injured tissues. Due to its ability to bind multiple ligands present in the tumor microenvironment, it promotes multiple cellular functions related to tumorigenesis. Recent data has shown that CD44 and its [...] Read more.
CD44 is a multifunctional adhesion molecule typically upregulated in malignant, inflamed and injured tissues. Due to its ability to bind multiple ligands present in the tumor microenvironment, it promotes multiple cellular functions related to tumorigenesis. Recent data has shown that CD44 and its principal ligand hyaluronan (HA) are carried by extracellular vesicles (EV) derived from stem and tumor cells, but the role of CD44 in EV shedding has not been studied so far. To answer this question, we utilized CD44-negative human gastric carcinoma cell line MKN74 manipulated to stably express CD44 standard form (CD44s). The effect of CD44s expression on HA metabolism, EV secretion, morphology and growth of these cells was studied. Interestingly, HAS2 and HYAL2 expression levels were significantly upregulated in CD44s-expressing cells. Cell-associated HA levels were significantly increased, while HA levels in the culture medium of CD44s-positive cells was lower compared to CD44s-negative MOCK cells. CD44s expression had no significant effect on the proliferation capacity of cells, but cells showed diminished contact inhibition. Superresolution imaging revealed that CD44s and HA were accumulated on filopodia and EVs secreted from CD44s-positive cells, but no differences in total numbers of secreted EV between CD44s-negative and -positive cells was detected. In 3D cultures, CD44s-expressing cells had an enhanced invasion capacity in BME gel and increased spheroidal growth when cultured in collagen I gel. No significant differences in mitotic activity, tumor size or morphology were detected in CAM assays. However, a significant increase in HA staining coverage was detected in CD44s-positive tumors. Interestingly, CD44s-positive EVs embedded in HA-rich matrix were detected in the stromal areas of tumors. The results indicate that CD44s expression significantly increases the HA binding capacity of gastric cancer cells, while the secreted HA is downregulated. CD44s is also carried by EVs secreted by CD44s-expressing cells. These findings highlight the potential usefulness of CD44s and its ligands as multipurpose EV biomarkers, because they are upregulated in inflammatory, injured, and cancer cells and accumulate on the surface of EVs secreted in these situations. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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11 pages, 1654 KiB  
Article
Mycoplasma genitalium Infection and Chronic Inflammation in Human Prostate Cancer: Detection Using Prostatectomy and Needle Biopsy Specimens
by Makito Miyake, Kenta Ohnishi, Shunta Hori, Akiyo Nakano, Ryuichi Nakano, Hisakazu Yano, Sayuri Ohnishi, Takuya Owari, Yosuke Morizawa, Yoshitaka Itami, Yasushi Nakai, Takeshi Inoue, Satoshi Anai, Kazumasa Torimoto, Nobumichi Tanaka, Tomomi Fujii, Hideki Furuya, Charles J. Rosser and Kiyohide Fujimoto
Cells 2019, 8(3), 212; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8030212 - 02 Mar 2019
Cited by 50 | Viewed by 7074
Abstract
The evidence of association between sexually transmitted infection and prostatic inflammation in human prostate cancer (PCa) is limited. Here, we sought to examine the potential association of prostatic infection with the inflammatory environment and prostate carcinogenesis. We screened surgical and biopsy specimens from [...] Read more.
The evidence of association between sexually transmitted infection and prostatic inflammation in human prostate cancer (PCa) is limited. Here, we sought to examine the potential association of prostatic infection with the inflammatory environment and prostate carcinogenesis. We screened surgical and biopsy specimens from 45 patients with PCa against a panel of sexually transmitted infection-related organisms using polymerase chain reaction and examined the severity of intraprostatic inflammation by pathologic examination. Among tested organisms, the rate of Mycoplasma genitalium (Mg) infection was significantly different between the prostate cancer cohort and benign prostate hyperplasia (BPH) cohort (P = 0.03). Mg infection in the surgical specimens was associated with younger patients. The rate of extensive disease (pT2c–3b) was higher in Mg-positive patients than in Mg-negative patients (P = 0.027). No significant correlation was observed between Mg infection status and the grade of intraprostatic inflammation. The detection sensitivity of biopsy specimens was 61% for Mg and 60% for human papillomavirus (HPV)18, indicating possible clinical application of this material. A comprehensive understanding of the correlation between the urogenital microbiome and inflammation would facilitate the development of strategies for PCa prevention. Further studies are required to explore its clinical utility in recommendations of early re-biopsy, close follow-up, and treatment by antibiotics. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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Review

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13 pages, 902 KiB  
Review
Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges
by Muhammad Zaeem Noman, Meriem Hasmim, Audrey Lequeux, Malina Xiao, Caroline Duhem, Salem Chouaib, Guy Berchem and Bassam Janji
Cells 2019, 8(9), 1083; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091083 - 14 Sep 2019
Cited by 145 | Viewed by 9116
Abstract
Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment [...] Read more.
Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment and its contribution to shaping the response to various anti-cancer therapies, including immunotherapy. Nevertheless, it has become clear that the tumor microenvironment is one of the main hallmarks of cancer. Therefore, a major challenge is to identify key druggable factors and pathways in the tumor microenvironment that can be manipulated to improve the efficacy of current cancer therapies. Among the different tumor microenvironmental factors, this review will focus on hypoxia as a key process that evolved in the tumor microenvironment. We will briefly describe our current understanding of the molecular mechanisms by which hypoxia negatively affects tumor immunity and shapes the anti-tumor immune response. We believe that such understanding will provide insight into the therapeutic value of targeting hypoxia and assist in the design of innovative combination approaches to improve the efficacy of current cancer therapies, including immunotherapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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9 pages, 778 KiB  
Review
The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment
by Valérie Molinier-Frenkel, Armelle Prévost-Blondel and Flavia Castellano
Cells 2019, 8(7), 757; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8070757 - 20 Jul 2019
Cited by 44 | Viewed by 7987
Abstract
The high metabolic needs of T lymphocytes in response to activation make them particularly vulnerable to modifications of their biochemical milieu. Immunosuppressive enzymes produced in the tumor microenvironment modify nutrient availability by catabolizing essential or semi-essential amino acids and producing toxic catabolites, thus [...] Read more.
The high metabolic needs of T lymphocytes in response to activation make them particularly vulnerable to modifications of their biochemical milieu. Immunosuppressive enzymes produced in the tumor microenvironment modify nutrient availability by catabolizing essential or semi-essential amino acids and producing toxic catabolites, thus participating in the local sabotage of the antitumor immune response. L-amino-acid oxidases are FAD-bound enzymes found throughout evolution, from bacteria to mammals, and are often endowed with anti-infectious properties. IL4I1 is a secreted L-phenylalanine oxidase mainly produced by inflammatory antigen-presenting cells—in particular, macrophages present in T helper type 1 granulomas and in various types of tumors. In the last decade, it has been shown that IL4I1 is involved in the fine control of B- and T-cell adaptive immune responses. Preclinical models have revealed its role in cancer immune evasion. Recent clinical data highlight IL4I1 as a new potential prognostic marker in human melanoma. As a secreted enzyme, IL4I1 may represent an easily targetable molecule for cancer immunotherapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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17 pages, 731 KiB  
Review
The Distinct Roles of CXCR3 Variants and Their Ligands in the Tumor Microenvironment
by Nathan Reynders, Dayana Abboud, Alessandra Baragli, Muhammad Zaeem Noman, Bernard Rogister, Simone P. Niclou, Nikolaus Heveker, Bassam Janji, Julien Hanson, Martyna Szpakowska and Andy Chevigné
Cells 2019, 8(6), 613; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060613 - 18 Jun 2019
Cited by 62 | Viewed by 10765
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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16 pages, 1070 KiB  
Review
Hypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells
by Pit Ullmann, Martin Nurmik, Rubens Begaj, Serge Haan and Elisabeth Letellier
Cells 2019, 8(6), 528; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060528 - 01 Jun 2019
Cited by 63 | Viewed by 5505
Abstract
Colorectal cancer (CRC), the second most common cause of cancer mortality in the Western world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Over the past [...] Read more.
Colorectal cancer (CRC), the second most common cause of cancer mortality in the Western world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Over the past few years, a plethora of different approaches, aimed at identifying and eradicating these self-renewing TICs, have been described. A focus on the metabolic and bioenergetic differences between TICs and less aggressive differentiated cancer cells has thereby emerged as a promising strategy to specifically target the tumorigenic cell compartment. Extrinsic factors, such as nutrient availability or tumor hypoxia, are known to influence the metabolic state of TICs. In this review, we aim to summarize the current knowledge on environmental stress factors and how they affect the metabolism of TICs, with a special focus on microRNA (miRNA)- and hypoxia-induced effects on colon TICs. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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28 pages, 2033 KiB  
Review
Hematological Malignancy-Derived Small Extracellular Vesicles and Tumor Microenvironment: The Art of Turning Foes into Friends
by Ernesto Gargiulo, Jerome Paggetti and Etienne Moussay
Cells 2019, 8(5), 511; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050511 - 27 May 2019
Cited by 28 | Viewed by 6663
Abstract
Small extracellular vesicles (small EVs) are commonly released by all cells, and are found in all body fluids. They are implicated in cell to cell short- and long-distance communication through the transfer of genetic material and proteins, as well as interactions between target [...] Read more.
Small extracellular vesicles (small EVs) are commonly released by all cells, and are found in all body fluids. They are implicated in cell to cell short- and long-distance communication through the transfer of genetic material and proteins, as well as interactions between target cell membrane receptors and ligands anchored on small EV membrane. Beyond their canonical functions in healthy tissues, small EVs are strategically used by tumors to communicate with the cellular microenvironment and to establish a proper niche which would ultimately allow cancer cell proliferation, escape from the immune surveillance, and metastasis formation. In this review, we highlight the effects of hematological malignancy-derived small EVs on immune and stromal cells in the tumor microenvironment. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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38 pages, 8759 KiB  
Review
Mitophagy in Cancer: A Tale of Adaptation
by Monica Vara-Perez, Blanca Felipe-Abrio and Patrizia Agostinis
Cells 2019, 8(5), 493; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050493 - 22 May 2019
Cited by 146 | Viewed by 15918
Abstract
In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cells plays a pivotal role in cancer initiation, progression and treatment response. Among the players involved, the pathways regulating mitochondrial [...] Read more.
In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cells plays a pivotal role in cancer initiation, progression and treatment response. Among the players involved, the pathways regulating mitochondrial functions have been shown to be crucial for both cancer and stromal cells. This is perhaps not surprising, considering that mitochondria in both cancerous and non-cancerous cells are decisive for vital metabolic and bioenergetic functions and to elicit cell death. The central part played by mitochondria also implies the existence of stringent mitochondrial quality control mechanisms, where a specialized autophagy pathway (mitophagy) ensures the selective removal of damaged or dysfunctional mitochondria. Although the molecular underpinnings of mitophagy regulation in mammalian cells remain incomplete, it is becoming clear that mitophagy pathways are intricately linked to the metabolic rewiring of cancer cells to support the high bioenergetic demand of the tumor. In this review, after a brief introduction of the main mitophagy regulators operating in mammalian cells, we discuss emerging cell autonomous roles of mitochondria quality control in cancer onset and progression. We also discuss the relevance of mitophagy in the cellular crosstalk with the tumor microenvironment and in anti-cancer therapy responses. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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17 pages, 719 KiB  
Review
Actin Cytoskeleton Straddling the Immunological Synapse between Cytotoxic Lymphocytes and Cancer Cells
by Hannah Wurzer, Céline Hoffmann, Antoun Al Absi and Clément Thomas
Cells 2019, 8(5), 463; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050463 - 16 May 2019
Cited by 37 | Viewed by 9020
Abstract
The immune system is a fundamental part of the tumor microenvironment. In particular, cytotoxic lymphocytes, such as cytolytic T cells and natural killer cells, control tumor growth and disease progression by interacting and eliminating tumor cells. The actin cytoskeleton of cytotoxic lymphocytes engaged [...] Read more.
The immune system is a fundamental part of the tumor microenvironment. In particular, cytotoxic lymphocytes, such as cytolytic T cells and natural killer cells, control tumor growth and disease progression by interacting and eliminating tumor cells. The actin cytoskeleton of cytotoxic lymphocytes engaged in an immunological synapse has received considerable research attention. It has been recognized as a central mediator of the formation and maturation of the immunological synapse, and its signaling and cytolytic activities. In comparison, fewer studies have explored the organization and function of actin filaments on the target cancer cell side of the immunological synapse. However, there is growing evidence that the actin cytoskeleton of cancer cells also undergoes extensive remodeling upon cytotoxic lymphocyte attack, and that such remodeling can alter physical and functional interactions at the immunological synapse. In this article, we review the current knowledge of actin organization and functions at both sides of the immunological synapse between cytotoxic lymphocytes and cancer cells, with particular focus on synapse formation, signaling and cytolytic activity, and immune evasion. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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20 pages, 627 KiB  
Review
The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System
by Elisabetta Romeo, Carmelo Antonio Caserta, Cristiano Rumio and Fabrizio Marcucci
Cells 2019, 8(5), 460; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050460 - 15 May 2019
Cited by 66 | Viewed by 4887
Abstract
Carcinoma cells that undergo an epithelial-mesenchymal transition (EMT) and display a predominantly mesenchymal phenotype (hereafter EMT tumor cells) are associated with immune exclusion and immune deviation in the tumor microenvironment (TME). A large body of evidence has shown that EMT tumor cells and [...] Read more.
Carcinoma cells that undergo an epithelial-mesenchymal transition (EMT) and display a predominantly mesenchymal phenotype (hereafter EMT tumor cells) are associated with immune exclusion and immune deviation in the tumor microenvironment (TME). A large body of evidence has shown that EMT tumor cells and immune cells can reciprocally influence each other, with EMT cells promoting immune exclusion and deviation and immune cells promoting, under certain circumstances, the induction of EMT in tumor cells. This cross-talk between EMT tumor cells and immune cells can occur both between EMT tumor cells and cells of either the native or adaptive immune system. In this article, we review this evidence and the functional consequences of it. We also discuss some recent evidence showing that tumor cells and cells of the immune system respond to similar stimuli, activate the expression of partially overlapping gene sets, and acquire, at least in part, identical functionalities such as migration and invasion. The possible significance of these symmetrical changes in the cross-talk between EMT tumor cells and immune cells is addressed. Eventually, we also discuss possible therapeutic opportunities that may derive from disrupting this cross-talk. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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20 pages, 2164 KiB  
Review
The B-Side of Cancer Immunity: The Underrated Tune
by Anne Largeot, Giulia Pagano, Susanne Gonder, Etienne Moussay and Jerome Paggetti
Cells 2019, 8(5), 449; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050449 - 13 May 2019
Cited by 106 | Viewed by 9394
Abstract
Tumor-infiltrating lymphocytes are known to be critical in controlling tumor progression. While the role of T lymphocytes has been extensively studied, the function of B cells in this context is still ill-defined. In this review, we propose to explore the role of B [...] Read more.
Tumor-infiltrating lymphocytes are known to be critical in controlling tumor progression. While the role of T lymphocytes has been extensively studied, the function of B cells in this context is still ill-defined. In this review, we propose to explore the role of B cells in tumor immunity. First of all we define their dual role in promoting and inhibiting cancer progression depending on their phenotype. To continue, we describe the influence of different tumor microenvironment factors such as hypoxia on B cells functions and differentiation. Finally, the role of B cells in response to therapy and as potential target is examined. In accordance with the importance of B cells in immuno-oncology, we conclude that more studies are required to throw light on the precise role of B cells in the tumor microenvironment in order to have a better understanding of their functions, and to design new strategies that efficiently target these cells by immunotherapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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20 pages, 1946 KiB  
Review
Strategies to Interfere with Tumor Metabolism through the Interplay of Innate and Adaptive Immunity
by Javier Mora, Christina Mertens, Julia K. Meier, Dominik C. Fuhrmann, Bernhard Brüne and Michaela Jung
Cells 2019, 8(5), 445; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050445 - 11 May 2019
Cited by 19 | Viewed by 5171
Abstract
The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory [...] Read more.
The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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