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Tumor Microenvironment from a Precision Medicine Perspective

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 40773

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Special Issue Editors

Dr. Alexander Deutsch

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Guest Editor

Division of Hematology, Medical University Graz, Auenbruggerplatz 38, 8036 Graz, Austria
Interests: tumor biology; molecular pathogenesis of indolent and aggressive lymphoma; tumor infiltrating immune cells; tumor immunology; chemokines and chemokine receptors; apoptosis
Special Issues, Collections and Topics in MDPI journals

Dr. Julia Feichtinger

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Division of Cell Biology, Histology and Embryology Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging Medical University of Graz, Graz, Austria
Interests: bioinformatics and big data analysis; comparative (epi)genomics and transcriptomics; public data mining, biomarker discovery; gene regulation and its dysregulation in diseases; tumor biology and heterogeneity with a focus on lymphomas; germline gene activation in tumors; long non-coding RNAs with a focus on antisense transcripts
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Dr. Jelena Krstic

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Department of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, Graz, Austria
Interests: tumor metabolism; tumor heterogeneity; therapy resistance; tumor evolution; metabolic targets and therapies; dietary interventions and cancer
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Dr. Katharina Prochazka

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Guest Editor

Medizinische Universität Graz, Graz, Austria
Interests: lymphoma; chemotherapy; DLBCL; - survival; immunotherapy; targeted Therapy; prognosis; CAR T-cells

Special Issue Information

Dear Colleagues,

Tumor biology research has increasingly focused on the tumor microenvironment—a complex network of resident and infiltrating non-malignant host cells, extracellular matrix proteins, and secreted factors within and around a tumor. The tumor microenvironment has a highly dynamic composition and delivers survival, proliferation, and/or immune modulatory signals to malignant cells via cellular interactions, secreted proteins, and metabolites. This intricate interplay also defines distinct niches in different malignancies and individual patients.

This Special Issue will host review, opinion, and research articles that focus on the composition of the tumor microenvironment, especially in relation to therapeutic and diagnostic approaches. We particularly welcome articles exploring strategies to define individual liabilities related to tumor microenvironment and tumor interactions, with personalized therapies as the final outcome. Special attention will be given to articles based on interdisciplinary research, e.g., (pre)clinical models in combination with omics, imaging, and/or bioinformatics analyses.

Dr. Alexander Deutsch
Dr. Julia Feichtinger
Dr. Jelena Krstic
Dr. Katharina Prochazka
Guest Editors

Manuscript Submission Information

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Keywords

tumor microenvironment and heterogeneity
therapeutic approaches targeting the tumor microenvironment
biomarkers for therapy and diagnostics
therapy resistance
personalized medicine
tumor immunology
metabolic plasticity of tumor microenvironment
bioinformatics in the field of cancer

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Published Papers (9 papers)

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Research

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13 pages, 15254 KiB

Open AccessArticle

Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2–EphB4 Signaling in Melanoma Metastatic Spine Disease

by Andras Piffko, Thomas Broggini, Christoph Harms, Ralf Heinrich Adams, Peter Vajkoczy and Marcus Czabanka

Int. J. Mol. Sci. 2021, 22(15), 8028; https://doi.org/10.3390/ijms22158028 - 27 Jul 2021

Cited by 3 | Viewed by 2009

Abstract

Tumor–endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2–EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2–EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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14 pages, 3320 KiB

Open AccessArticle

VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms

by Tijana Subotički, Olivera Mitrović Ajtić, Emilija Živković, Miloš Diklić, Dragoslava Đikić, Milica Tošić, Bojana Beleslin-Čokić, Teodora Dragojević, Mirjana Gotić, Juan F. Santibanez and Vladan Čokić

Int. J. Mol. Sci. 2021, 22(13), 6671; https://doi.org/10.3390/ijms22136671 - 22 Jun 2021

Cited by 15 | Viewed by 2396

Abstract

Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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14 pages, 1679 KiB

Open AccessArticle

Evidence for Non-Cancer-Specific T Cell Exhaustion in the Tcl1 Mouse Model for Chronic Lymphocytic Leukemia

by Thomas Parigger, Franz Josef Gassner, Christian Scherhäufl, Aryunni Abu Bakar, Jan Philip Höpner, Alexandra Hödlmoser, Markus Steiner, Kemal Catakovic, Roland Geisberger, Richard Greil and Nadja Zaborsky

Int. J. Mol. Sci. 2021, 22(13), 6648; https://doi.org/10.3390/ijms22136648 - 22 Jun 2021

Cited by 3 | Viewed by 2587

Abstract

The reinvigoration of anti-cancer immunity by immune checkpoint therapies has greatly improved cancer treatment. In chronic lymphocytic leukemia (CLL), patients as well as in the Tcl1 mouse model for CLL, PD1-expressing, exhausted T cells significantly expand alongside CLL development; nevertheless, PD1 inhibition has no clinical benefit. Hence, exhausted T cells are either not activatable by simple PD1 blocking in CLL and/or only an insufficient number of exhausted T cells are CLL-specific. In this study, we examined the latter hypothesis by exploiting the Tcl1 transgenic CLL mouse model in combination with TCR transgene expression specific for a non-cancer antigen. Following CLL tumor development, increased PD1 levels were detected on non-CLL specific T cells that seem dependent on the presence of (tumor-) antigen-specific T cells. Transcriptome analysis confirmed a similar exhaustion phenotype of non-CLL specific and endogenous PD1pos T cells. Our results indicate that in the CLL mouse model, a substantial fraction of non-CLL specific T cells becomes exhausted during disease progression in a bystander effect. These findings have important implications for the general efficacy assessment of immune checkpoint therapies in CLL. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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18 pages, 3066 KiB

Open AccessArticle

Characteristics of Malignant Pleural Effusion Resident CD8⁺ T Cells from a Heterogeneous Collection of Tumors

by Rajeev Dhupar, Olugbenga T. Okusanya, Seth H. Eisenberg, Sara E. Monaco, Ayana T. Ruffin, Dongyan Liu, James D. Luketich, Udai S. Kammula, Tullia C. Bruno, Michael T. Lotze and Adam C. Soloff

Int. J. Mol. Sci. 2020, 21(17), 6178; https://doi.org/10.3390/ijms21176178 - 27 Aug 2020

Cited by 12 | Viewed by 3370

Abstract

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 10⁸ leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8⁺ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8⁺ T cells with autologous CD45^― tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8⁺ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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Review

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51 pages, 1586 KiB

Open AccessReview

Immune Regulatory Processes of the Tumor Microenvironment under Malignant Conditions

by Katrin Pansy, Barbara Uhl, Jelena Krstic, Marta Szmyra, Karoline Fechter, Ana Santiso, Lea Thüminger, Hildegard Greinix, Julia Kargl, Katharina Prochazka, Julia Feichtinger and Alexander JA. Deutsch

Int. J. Mol. Sci. 2021, 22(24), 13311; https://doi.org/10.3390/ijms222413311 - 10 Dec 2021

Cited by 63 | Viewed by 9840

Abstract

The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Since immune cells represent a large fraction of the TME, they play a key role in mediating pro- and anti-tumor immune responses. Immune escape, which suppresses anti-tumor immunity, enables tumor cells to maintain their proliferation and growth. Numerous mechanisms, which have been intensively studied in recent years, are involved in this process and based on these findings, novel immunotherapies have been successfully developed. Here, we review the composition of the TME and the mechanisms by which immune evasive processes are regulated. In detail, we describe membrane-bound and soluble factors, their regulation, and their impact on immune cell activation in the TME. Furthermore, we give an overview of the tumor/antigen presentation and how it is influenced under malignant conditions. Finally, we summarize novel TME-targeting agents, which are already in clinical trials for different tumor entities. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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22 pages, 1907 KiB

Open AccessReview

Immunomodulatory Drugs for the Treatment of B Cell Malignancies

by Nikolaos Ioannou, Khushi Jain and Alan G. Ramsay

Int. J. Mol. Sci. 2021, 22(16), 8572; https://doi.org/10.3390/ijms22168572 - 9 Aug 2021

Cited by 26 | Viewed by 6043

Abstract

Accumulating evidence suggests that the tumor microenvironment (TME) is involved in disease progression and drug resistance in B cell malignancies, by supporting tumor growth and facilitating the ability of malignant cells to avoid immune recognition. Immunomodulatory drugs (IMiDs) such as lenalidomide have some direct anti-tumor activity, but critically also target various cellular compartments of the TME including T cells, NK cells, and stromal cells, which interfere with pro-tumor signaling while activating anti-tumor immune responses. Lenalidomide has delivered favorable clinical outcomes as a single-agent, and in combination therapy leads to durable responses in chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphomas (NHLs) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Recently, avadomide, a next generation cereblon E3 ligase modulator (CELMoD), has shown potent anti-tumor and TME immunomodulatory effects, as well as promising clinical efficacy in DLBCL. This review describes how the pleiotropic effects of IMiDs and CELMoDs could make them excellent candidates for combination therapy in the immuno-oncology era—a concept supported by preclinical data, as well as the recent approval of lenalidomide in combination with rituximab for the treatment of relapsed/refractory (R/R) FL. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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19 pages, 1140 KiB

Open AccessReview

MicroRNAs in Epithelial–Mesenchymal Transition Process of Cancer: Potential Targets for Chemotherapy

by Fu Peng, Huali Fan, Sui Li, Cheng Peng and Xiaoqi Pan

Int. J. Mol. Sci. 2021, 22(14), 7526; https://doi.org/10.3390/ijms22147526 - 14 Jul 2021

Cited by 13 | Viewed by 2703

Abstract

In the last decades, a kind of small non-coding RNA molecules, called as microRNAs, has been applied as negative regulators in various types of cancer treatment through down-regulation of their targets. More recent studies exert that microRNAs play a critical role in the EMT process of cancer, promoting or inhibiting EMT progression. Interestingly, accumulating evidence suggests that pure compounds from natural plants could modulate deregulated microRNAs to inhibit EMT, resulting in the inhibition of cancer development. This small essay is on the purpose of demonstrating the significance and function of microRNAs in the EMT process as oncogenes and tumor suppressor genes according to studies mainly conducted in the last four years, providing evidence of efficient target therapy. The review also summarizes the drug candidates with the ability to restrain EMT in cancer through microRNA regulation. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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16 pages, 332 KiB

Open AccessReview

Prognostic and Predictive Factors in Advanced Head and Neck Squamous Cell Carcinoma

by Teresa Magnes, Sandro Wagner, Dominik Kiem, Lukas Weiss, Gabriel Rinnerthaler, Richard Greil and Thomas Melchardt

Int. J. Mol. Sci. 2021, 22(9), 4981; https://doi.org/10.3390/ijms22094981 - 7 May 2021

Cited by 39 | Viewed by 5617

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

19 pages, 2131 KiB

Open AccessReview

Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment

by Gabriele Grasmann, Ayusi Mondal and Katharina Leithner

Int. J. Mol. Sci. 2021, 22(3), 1476; https://doi.org/10.3390/ijms22031476 - 2 Feb 2021

Cited by 28 | Viewed by 4983

Abstract

The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell proliferation and survival. A large body of evidence from recent studies suggests that tumor cells show a high degree of metabolic flexibility and adapt to variations in nutrient availability. Insufficient vascular networks and an imbalance of supply and demand shape the metabolic tumor microenvironment, which typically contains a lower concentration of glucose compared to normal tissues. The present review sheds light on the recent literature on adaptive responses in cancer cells to nutrient deprivation. It focuses on the utilization of alternative nutrients in anabolic metabolic pathways in cancer cells, including soluble metabolites and macromolecules and outlines the role of central metabolic enzymes conferring metabolic flexibility, like gluconeogenesis enzymes. Moreover, a conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective)

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