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Tumor Microenvironment from a Precision Medicine Perspective 2.0

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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 (31 October 2022) | Viewed by 28330

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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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Guest Editor

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
Special Issues, Collections and Topics in MDPI journals

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.

As volume 1 of special issue “Tumor Microenvironment from a Precision Medicine Perspective” is successful we reopen this issue again in the International Journal of Molecular Sciences (https://www.mdpi.com/journal/ijms, ISSN 1422-0067, IF 5.923, JCR Category Q1). This second 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.

https://www.mdpi.com/journal/ijms/special_issues/tumor_micro

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

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

Published Papers (9 papers)

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Research

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12 pages, 2385 KiB

Open AccessArticle

Precision Medicine: Determination of Ribavirin Urinary Metabolites in Relation to Drug Adverse Effects in HCV Patients

by Ottavia Giampaoli, Fabio Sciubba, Elisa Biliotti, Mariangela Spagnoli, Riccardo Calvani, Alberta Tomassini, Giorgio Capuani, Alfredo Miccheli and Gloria Taliani

Int. J. Mol. Sci. 2022, 23(17), 10043; https://doi.org/10.3390/ijms231710043 - 2 Sep 2022

Cited by 2 | Viewed by 1631

Abstract

The most commonly used antiviral treatment against hepatitis C virus is a combination of direct-acting antivirals (DAAs) and ribavirin (RBV), which leads to a shortened duration of therapy and a sustained virologic response until 98%. Nonetheless, several dose-related side effects of RBV could limit its applications. This study aims to measure the urinary concentration of RBV and its main metabolites in order to evaluate the drug metabolism ability of HCV patients and to evaluate the adverse effects, such as anemia, with respect to RBV metabolite levels. RBV and its proactive and inactive metabolites were identified and quantified in the urine of 17 HCV males with severe liver fibrosis using proton nuclear magnetic resonance (¹H-NMR) at the fourth week (TW4) and at the twelfth week of treatment (EOT). Four prodrug urinary metabolites, including RBV, were identified and three of them were quantified. At both the TW4 and EOT stages, six HCV patients were found to maintain high concentrations of RBV, while another six patients maintained a high level of RBV proactive metabolites, likely due to nucleosidase activity. Furthermore, a negative correlation between the reduction in hemoglobin (Hb) and proactive forms was observed, according to RBV-triphosphate accumulation causing the hemolysis. These findings represent a proof of concept regarding tailoring the drug dose in relation to the specific metabolic ability of the individual, as expected by the precision medicine approach. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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22 pages, 25391 KiB

Open AccessArticle

Senescent Human Pancreatic Stellate Cells Secrete CXCR2 Agonist CXCLs to Promote Proliferation and Migration of Human Pancreatic Cancer AsPC-1 and MIAPaCa-2 Cell Lines

by Tetsuya Takikawa, Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Fumiya Kataoka, Akira Sasaki and Atsushi Masamune

Int. J. Mol. Sci. 2022, 23(16), 9275; https://doi.org/10.3390/ijms23169275 - 17 Aug 2022

Cited by 9 | Viewed by 2175

Abstract

Interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) play an important role in the progression of pancreatic cancer. Recent studies have shown that cellular senescence and senescence-associated secretory phenotype factors play roles in the progression of cancer. This study aimed to clarify the effects of senescence-induced PSCs on pancreatic cancer cells. Senescence was induced in primary-cultured human PSCs (hPSCs) through treatment with hydrogen peroxide or gemcitabine. Microarray and Gene Ontology analyses showed the alterations in genes and pathways related to cellular senescence and senescence-associated secretory phenotype factors, including the upregulation of C-X-C motif chemokine ligand (CXCL)-1, CXCL2, and CXCL3 through the induction of senescence in hPSCs. Conditioned media of senescent hPSCs increased the proliferation—as found in an assessment with a BrdU incorporation assay—and migration—as found in an assessment with wound-healing and two-chamber assays—of pancreatic cancer AsPC-1 and MIAPaca-2 cell lines. SB225002, a selective CXCR2 antagonist, and SCH-527123, a CXCR1/CXCR2 antagonist, attenuated the effects of conditioned media of senescent hPSCs on the proliferation and migration of pancreatic cancer cells. These results suggest a role of CXCLs as senescence-associated secretory phenotype factors in the interaction between senescent hPSCs and pancreatic cancer cells. Senescent PSCs might be novel therapeutic targets for pancreatic cancer. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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17 pages, 4178 KiB

Open AccessArticle

Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter’s Trans-Formed DLBCL and Germinal Center B-Cells

by Barbara Uhl, Katharina T. Prochazka, Katrin Pansy, Kerstin Wenzl, Johanna Strobl, Claudia Baumgartner, Marta M. Szmyra, James E. Waha, Axel Wolf, Peter V. Tomazic, Elisabeth Steinbauer, Maria Steinwender, Sabine Friedl, Marc Weniger, Ralf Küppers, Martin Pichler, Hildegard T. Greinix, Georg Stary, Alan G. Ramsay, Benedetta Apollonio, Julia Feichtinger, Christine Beham-Schmid, Peter Neumeister and Alexander J. Deutsch Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(14), 7874; https://doi.org/10.3390/ijms23147874 - 17 Jul 2022

Cited by 2 | Viewed by 2479

Abstract

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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Review

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29 pages, 1243 KiB

Open AccessReview

Hyaluronic Acid as a Modern Approach in Anticancer Therapy-Review

by Monika Michalczyk, Ewelina Humeniuk, Grzegorz Adamczuk and Agnieszka Korga-Plewko

Int. J. Mol. Sci. 2023, 24(1), 103; https://doi.org/10.3390/ijms24010103 - 21 Dec 2022

Cited by 21 | Viewed by 3146

Abstract

Hyaluronic acid (HA) is a linear polysaccharide and crucial component of the extracellular matrix (ECM), maintaining tissue hydration and tension. Moreover, HA contributes to embryonic development, healing, inflammation, and cancerogenesis. This review summarizes new research on the metabolism and interactions of HA with its binding proteins, known as hyaladherins (CD44, RHAMM), revealing the molecular basis for its distinct biological function in the development of cancer. The presence of HA on the surface of tumor cells is a sign of an adverse prognosis. The involvement of HA in malignancy has been extensively investigated using cancer-free naked mole rats as a model. The HA metabolic components are examined for their potential impact on promoting or inhibiting tumor formation, proliferation, invasion, and metastatic spread. High molecular weight HA is associated with homeostasis and protective action due to its ability to preserve tissue integrity. In contrast, low molecular weight HA indicates a pathological condition in the tissue and plays a role in pro-oncogenic activity. A systematic approach might uncover processes related to cancer growth, establish novel prognostic indicators, and identify potential targets for treatment action. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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19 pages, 1469 KiB

Open AccessReview

Targeting the Microenvironment for Treating Multiple Myeloma

by Peter Neumeister, Eduard Schulz, Katrin Pansy, Marta Szmyra and Alexander JA Deutsch

Int. J. Mol. Sci. 2022, 23(14), 7627; https://doi.org/10.3390/ijms23147627 - 10 Jul 2022

Cited by 13 | Viewed by 5028

Abstract

Multiple myeloma (MM) is a malignant, incurable disease characterized by the expansion of monoclonal terminally differentiated plasma cells in the bone marrow. MM is consistently preceded by an asymptomatic monoclonal gammopathy of undetermined significance, and in the absence of myeloma defining events followed by a stage termed smoldering multiple myeloma (SMM), which finally progresses to active myeloma if signs of organ damage are present. The reciprocal interaction between tumor cells and the tumor microenvironment plays a crucial role in the development of MM and the establishment of a tumor-promoting stroma facilitates tumor growth and myeloma progression. Since myeloma cells depend on signals from the bone marrow microenvironment (BMME) for their survival, therapeutic interventions targeting the BMME are a novel and successful strategy for myeloma care. Here, we describe the complex interplay between myeloma cells and the cellular components of the BMME that is essential for MM development and progression. Finally, we present BMME modifying treatment options such as anti-CD38 based therapies, immunomodulatory drugs (IMiDs), CAR T-cell therapies, bispecific antibodies, and antibody-drug conjugates which have significantly improved the long-term outcome of myeloma patients, and thus represent novel therapeutic standards. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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19 pages, 112028 KiB

Open AccessReview

The Morpho-Molecular Landscape of Spitz Neoplasms

by Carlo Alberto Dal Pozzo and Rocco Cappellesso

Int. J. Mol. Sci. 2022, 23(8), 4211; https://doi.org/10.3390/ijms23084211 - 11 Apr 2022

Cited by 12 | Viewed by 3598

Abstract

Spitz neoplasms are a heterogeneous group of melanocytic proliferations with a great variability in the histological characteristics and in the biological behavior. Thanks to recent discoveries, the morpho-molecular landscape of Spitz lineage is becoming clearer, with the identification of subtypes with recurrent features thus providing the basis for a more solid and precise tumor classification. Indeed, specific mutually exclusive driver molecular events, namely HRAS or MAP2K1 mutations, copy number gains of 11p, and fusions involving ALK, ROS, NTRK1, NTRK2, NTRK3, MET, RET, MAP3K8, and BRAF genes, correlate with distinctive histological features. The accumulation of further molecular aberrations, instead, promotes the increasing malignant transformation of Spitz neoplasms. Thus, the detection of a driver genetic alteration can be achieved using the appropriate diagnostic tests chosen according to the histological characteristics of the lesion. This allows the recognition of subtypes with aggressive behavior requiring further molecular investigations. This review provides an update on the morpho-molecular correlations in Spitz neoplasms. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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17 pages, 1312 KiB

Open AccessReview

Activity of ALK Inhibitors in Renal Cancer with ALK Alterations: A Systematic Review

by Giovanni Maria Iannantuono, Silvia Riondino, Stefano Sganga, Mario Roselli and Francesco Torino

Int. J. Mol. Sci. 2022, 23(7), 3995; https://doi.org/10.3390/ijms23073995 - 3 Apr 2022

Cited by 8 | Viewed by 2314

Abstract

Renal cell carcinoma (RCC) associated with anaplastic lymphoma kinase (ALK) gene rearrangements (ALK-RCC) is currently considered an “emerging or provisional” tumor entity by the last World Health Organization classification published in 2016. Although several studies assessing ALK-RCC’s clinical and histological characteristics have been published in recent years, only a few publications have evaluated the activity of ALK inhibitors (ALK-i) in this subgroup of patients. Considering the well-recognized efficacy of this evolving class of targeted therapies in other ALK-positive tumors, we conducted a systematic review to evaluate the reported activity of ALK-i in the ALK-RCC subtype. MEDLINE was searched from its inception to 7 January 2022 for case reports and case series on adult metastatic ALK-RCC patients treated with ALK-i whose therapeutic outcomes were available. A virtual cohort of ALK-RCC patients was created. Our results showed a favorable activity of first- and second-generation ALK-i in pretreated ALK-RCC patients in terms of either radiological response or performance status improvement. We hope that the present work will prompt the creation of large, multi-institutional clinical trials to confirm these promising early data. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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14 pages, 919 KiB

Open AccessReview

Exploring the FGF/FGFR System in Ocular Tumors: New Insights and Perspectives

by Alessandra Loda, Marta Turati, Francesco Semeraro, Sara Rezzola and Roberto Ronca

Int. J. Mol. Sci. 2022, 23(7), 3835; https://doi.org/10.3390/ijms23073835 - 30 Mar 2022

Cited by 7 | Viewed by 2854

Abstract

Ocular tumors are a family of rare neoplasms that develop in the eye. Depending on the type of cancer, they mainly originate from cells localized within the retina, the uvea, or the vitreous. Even though current treatments (e.g., radiotherapy, transpupillary thermotherapy, cryotherapy, chemotherapy, local resection, or enucleation) achieve the control of the local tumor in the majority of treated cases, a significant percentage of patients develop metastatic disease. In recent years, new targeting therapies and immuno-therapeutic approaches have been evaluated. Nevertheless, the search for novel targets and players is eagerly required to prevent and control tumor growth and metastasis dissemination. The fibroblast growth factor (FGF)/FGF receptor (FGFR) system consists of a family of proteins involved in a variety of physiological and pathological processes, including cancer. Indeed, tumor and stroma activation of the FGF/FGFR system plays a relevant role in tumor growth, invasion, and resistance, as well as in angiogenesis and dissemination. To date, scattered pieces of literature report that FGFs and FGFRs are expressed by a significant subset of primary eye cancers, where they play relevant and pleiotropic roles. In this review, we provide an up-to-date description of the relevant roles played by the FGF/FGFR system in ocular tumors and speculate on its possible prognostic and therapeutic exploitation. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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22 pages, 1056 KiB

Open AccessReview

Tumor-Mediated Neutrophil Polarization and Therapeutic Implications

by Sofia Raftopoulou, Paulina Valadez-Cosmes, Zala Nikita Mihalic, Rudolf Schicho and Julia Kargl

Int. J. Mol. Sci. 2022, 23(6), 3218; https://doi.org/10.3390/ijms23063218 - 16 Mar 2022

Cited by 19 | Viewed by 4284

Abstract

Neutrophils are immune cells with reported phenotypic and functional plasticity. Tumor-associated neutrophils display many roles during cancer progression. Several tumor microenvironment (TME)-derived factors orchestrate neutrophil release from the bone marrow, recruitment and functional polarization, while simultaneously neutrophils are active stimulators of the TME by secreting factors that affect immune interactions and subsequently tumor progression. Successful immunotherapies for many cancer types and stages depend on the targeting of tumor-infiltrating lymphocytes. Neutrophils impact the success of immunotherapies, such as immune checkpoint blockade therapies, by displaying lymphocyte suppressive properties. The identification and characterization of distinct neutrophil subpopulations or polarization states with pro- and antitumor phenotypes and the identification of the major TME-derived factors of neutrophil polarization would allow us to harness the full potential of neutrophils as complementary targets in anticancer precision therapies. Full article

(This article belongs to the Special Issue Tumor Microenvironment from a Precision Medicine Perspective 2.0)

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