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Cancers
Special Issues
Microenvironment and Cancer Progression 2.0
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Microenvironment and Cancer Progression 2.0

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 19256

Special Issue Editor

Prof. Dr. Jurgen Dittmer

E-Mail Website
Guest Editor
Clinic for Gynecology, University of Halle-Wittenberg, 06120 Halle, Germany
Interests: breast cancer; mesenchymal stem cells; carcinoma-associated fibroblasts; endocrine resistance; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of a previous release, “Microenvironment and Cancer Progression” (https://www.mdpi.com/journal/cancers/special_issues/microenviron_prog).

The importance of the cancer microenvironment for cancer progression is increasingly being appreciated. The cancer microenvironment has a tremendous impact on cancer cell behavior and plays a role in numerous cancer-related processes, such as cancer growth, invasion, neo-angiogenesis, drug resistance, and metastasis. Multiple interactions of cancer cells with different types of stromal cells and with the extracellular matrix form the basis by which the microenvironment influences cancer progression. A better understanding of these interactions may allow us to extend our cancer treatment arsenal with drugs targeting the cancer microenvironment.

This Special Issue, “Microenvironment and Cancer Progression 2.0”, aims to pool knowledge on the different mechanisms by which the cancer microenvironment modulates cancer cell behavior in primary as well as in metastatic cancer lesions. All scientists working in this field are cordially invited to submit their manuscripts.

Prof. Dr. Jurgen Dittmer
Guest Editor

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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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.

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Published Papers (7 papers)

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Research

Jump to: Review

12 pages, 5267 KiB  
Article
Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma
by Kathrin Maitz, Paulina Valadez-Cosmes, Sofia Raftopoulou, Oliver Kindler, Melanie Kienzl, Hamid Bolouri, A. McGarry Houghton, Rudolf Schicho, Akos Heinemann and Julia Kargl
Cancers 2023, 15(24), 5767; https://doi.org/10.3390/cancers15245767 - 8 Dec 2023
Cited by 2 | Viewed by 1518
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work [...] Read more.
Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aimed to explore the impact of DDR1 expression on immune cell infiltration in lung adenocarcinoma. Pharmacological inhibition and knockout of DDR1 were used in an immunocompetent mouse model of KRAS/p53-driven lung adenocarcinoma (LUAD). Tumor cells were engrafted subcutaneously, after which tumors were harvested for investigation of immune cell composition via flow cytometry. The Cancer Genome Atlas (TCGA) cohort was used to perform gene expression analysis of 509 patients with LUAD. Pharmacological inhibition and knockout of DDR1 increased the tumor burden, with DDR1 knockout tumors showing a decrease in CD8+ cytotoxic T cells and an increase in CD4+ helper T cells and regulatory T cells. TCGA analysis revealed that low-DDR1-expressing tumors showed higher FoxP3 (regulatory T-cell marker) expression than high-DDR1-expressing tumors. Our study showed that under certain conditions, the inhibition of DDR1, a potential therapeutic target in cancer treatment, might have negative effects, such as inducing a pro-tumorigenic tumor microenvironment. As such, further investigations are necessary. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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26 pages, 4472 KiB  
Article
Heterogeneity in the Metastatic Microenvironment: JunB-Expressing Microglia Cells as Potential Drivers of Melanoma Brain Metastasis Progression
by Orit Adir, Orit Sagi-Assif, Tsipi Meshel, Shlomit Ben-Menachem, Metsada Pasmanik-Chor, Dave S. B. Hoon, Isaac P. Witz and Sivan Izraely
Cancers 2023, 15(20), 4979; https://doi.org/10.3390/cancers15204979 - 13 Oct 2023
Cited by 2 | Viewed by 1655
Abstract
Reciprocal signaling between melanoma brain metastatic (MBM) cells and microglia reprograms the phenotype of both interaction partners, including upregulation of the transcription factor JunB in microglia. Here, we aimed to elucidate the impact of microglial JunB upregulation on MBM progression. For molecular profiling, [...] Read more.
Reciprocal signaling between melanoma brain metastatic (MBM) cells and microglia reprograms the phenotype of both interaction partners, including upregulation of the transcription factor JunB in microglia. Here, we aimed to elucidate the impact of microglial JunB upregulation on MBM progression. For molecular profiling, we employed RNA-seq and reverse-phase protein array (RPPA). To test microglial JunB functions, we generated microglia variants stably overexpressing JunB (JunBhi) or with downregulated levels of JunB (JunBlo). Melanoma-derived factors, namely leukemia inhibitory factor (LIF), controlled JunB upregulation through Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling. The expression levels of JunB in melanoma-associated microglia were heterogeneous. Flow cytometry analysis revealed the existence of basal-level JunB-expressing microglia alongside microglia highly expressing JunB. Proteomic profiling revealed a differential protein expression in JunBhi and JunBlo cells, namely the expression of microglia activation markers Iba-1 and CD150, and the immunosuppressive molecules SOCS3 and PD-L1. Functionally, JunBhi microglia displayed decreased migratory capacity and phagocytic activity. JunBlo microglia reduced melanoma proliferation and migration, while JunBhi microglia preserved the ability of melanoma cells to proliferate in three-dimensional co-cultures, that was abrogated by targeting leukemia inhibitory factor receptor (LIFR) in control microglia–melanoma spheroids. Altogether, these data highlight a melanoma-mediated heterogenous effect on microglial JunB expression, dictating the nature of their functional involvement in MBM progression. Targeting microglia highly expressing JunB may potentially be utilized for MBM theranostics. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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28 pages, 6669 KiB  
Article
Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro
by Madelaine Magalì Audero, Tiago Miguel Amaral Carvalho, Federico Alessandro Ruffinatti, Thorsten Loeck, Maya Yassine, Giorgia Chinigò, Antoine Folcher, Valerio Farfariello, Samuele Amadori, Chiara Vaghi, Albrecht Schwab, Stephan J. Reshkin, Rosa Angela Cardone, Natalia Prevarskaya and Alessandra Fiorio Pla
Cancers 2023, 15(9), 2572; https://doi.org/10.3390/cancers15092572 - 30 Apr 2023
Cited by 6 | Viewed by 2799
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an acidic microenvironment, which contributes to therapeutic failure. So far there is a lack of knowledge with respect to the role of the acidic microenvironment in the invasive process. This work aimed to study the phenotypic [...] Read more.
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an acidic microenvironment, which contributes to therapeutic failure. So far there is a lack of knowledge with respect to the role of the acidic microenvironment in the invasive process. This work aimed to study the phenotypic and genetic response of PDAC cells to acidic stress along the different stages of selection. To this end, we subjected the cells to short- and long-term acidic pressure and recovery to pHe 7.4. This treatment aimed at mimicking PDAC edges and consequent cancer cell escape from the tumor. The impact of acidosis was assessed for cell morphology, proliferation, adhesion, migration, invasion, and epithelial–mesenchymal transition (EMT) via functional in vitro assays and RNA sequencing. Our results indicate that short acidic treatment limits growth, adhesion, invasion, and viability of PDAC cells. As the acid treatment progresses, it selects cancer cells with enhanced migration and invasion abilities induced by EMT, potentiating their metastatic potential when re-exposed to pHe 7.4. The RNA-seq analysis of PANC-1 cells exposed to short-term acidosis and pHe-selected recovered to pHe 7.4 revealed distinct transcriptome rewiring. We describe an enrichment of genes relevant to proliferation, migration, EMT, and invasion in acid-selected cells. Our work clearly demonstrates that upon acidosis stress, PDAC cells acquire more invasive cell phenotypes by promoting EMT and thus paving the way for more aggressive cell phenotypes. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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16 pages, 4085 KiB  
Article
A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells
by Angela Dittmer and Jürgen Dittmer
Cancers 2022, 14(20), 4983; https://doi.org/10.3390/cancers14204983 - 11 Oct 2022
Cited by 8 | Viewed by 2447
Abstract
TIMP-1 is one of the many factors that CAFs have been shown to secret. TIMP-1 can act in a tumor-supportive or tumor-suppressive manner. The purpose of this study was to elucidate the role of CAF-secreted TIMP-1 for the effects of CAFs on breast [...] Read more.
TIMP-1 is one of the many factors that CAFs have been shown to secret. TIMP-1 can act in a tumor-supportive or tumor-suppressive manner. The purpose of this study was to elucidate the role of CAF-secreted TIMP-1 for the effects of CAFs on breast cancer cell behavior. Breast cancer cells were exposed to conditioned medium collected from TIMP-1-secreting CAFs (CAF-CM), and the specific effects of TIMP-1 on protein expression, migration and growth were examined using TIMP-1-specifc siRNA (siTIMP1), recombinant TIMP-1 protein (rhTIMP-1) and TIMP-1 level-rising phorbol ester. We observed that TIMP-1 increased the expression of its binding partner CD63 and induced STAT3 and ERK1/2 activation by cooperating with CD63 and integrin β1. Since TIMP-1 expression was found to be dependent on STAT3, TIMP-1 activated its own expression, resulting in a TIMP-1/CD63/integrin β1/STAT3 feedback loop. IL-6, a classical STAT3 activator, further fueled this loop. Knock-down of each component of the feedback loop prevented the CAF-induced increase in migratory activity and inhibited cellular growth in adherent cultures in the presence and absence of the anti-estrogen fulvestrant. These data show that TIMP-1/CD63/integrin β1/STAT3 plays a role in the effects of CAFs on breast cancer cell behavior. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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Review

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19 pages, 1233 KiB  
Review
The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy
by Brian D. Griffith and Timothy L. Frankel
Cancers 2024, 16(3), 472; https://doi.org/10.3390/cancers16030472 - 23 Jan 2024
Cited by 5 | Viewed by 2541
Abstract
The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of [...] Read more.
The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified. Although targeting AhR in cancer has shown significant promise in pre-clinical studies, there has been limited efficacy in phase III clinical trials to date. With the contrasting roles of AhR activation on immune cell polarization, understanding the impact of AhR activation on the tumor immune microenvironment is necessary to guide therapies targeting the AhR. This review article summarizes the state of knowledge of AhR activation on the TME, limitations of current findings, and the potential for modulation of the AhR as a cancer therapy. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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26 pages, 3840 KiB  
Review
Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice
by Anna Chen, Ines Neuwirth and Dietmar Herndler-Brandstetter
Cancers 2023, 15(11), 2989; https://doi.org/10.3390/cancers15112989 - 30 May 2023
Cited by 9 | Viewed by 4884
Abstract
Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular [...] Read more.
Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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13 pages, 987 KiB  
Review
Mycosis Fungoides and Sézary Syndrome: Microenvironment and Cancer Progression
by Gabor Dobos, Ingrid Lazaridou and Adèle de Masson
Cancers 2023, 15(3), 746; https://doi.org/10.3390/cancers15030746 - 25 Jan 2023
Cited by 7 | Viewed by 2655
Abstract
Mycosis fungoides and Sézary syndrome are epidermotropic cutaneous lymphomas, and both of them are rare diseases. Mycosis fungoides is the most frequent primary cutaneous lymphoma. In about 25% of patients with mycosis fungoides, the disease may progress to higher stages. The pathogenesis and [...] Read more.
Mycosis fungoides and Sézary syndrome are epidermotropic cutaneous lymphomas, and both of them are rare diseases. Mycosis fungoides is the most frequent primary cutaneous lymphoma. In about 25% of patients with mycosis fungoides, the disease may progress to higher stages. The pathogenesis and risk factors of progression in mycosis fungoides and Sézary syndrome are not yet fully understood. Previous works have investigated inter- and intrapatient tumor cell heterogeneity. Here, we overview the role of the tumor microenvironment of mycosis fungoides and Sézary syndrome by describing its key components and functions. Emphasis is put on the role of the microenvironment in promoting tumor growth or antitumor immune response, as well as possible therapeutic targets. We focus on recent advances in the field and point out treatment-related alterations of the microenvironment. Deciphering the tumor microenvironment may help to develop strategies that lead to long-term disease control and cure. Full article
(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)
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