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Biomedicines
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Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives
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Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 9203

Special Issue Editors

Dr. Adriana Grigoraș

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Guest Editor
Department of Histology, University of Medicine and Pharmacy "Gr. T. Popa” Iasi, Iasi, Romania
Interests: obesity-related pathology; tumor pathology; histology
Prof. Dr. Cornelia Amalinei

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Guest Editor
Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
Interests: pathology; cytology; histology; immunohistochemistry; carcinogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The tumor microenvironment is a complex ecosystem, which includes cancer-associated cells, blood vessels, and extracellular matrix, involving a large panel of cellular-derived factors. It also comprises different types of immune cells, such as T and B lymphocytes, natural killer (NK) cells, dendritic cells, myeloid-derived suppressor cells (MDSCs), neutrophils, and tumor-associated macrophages (TAMs). In addition, intercellular communication is supported by a large spectrum of chemokines, cytokines, inflammatory mediators, growth factors, and matrix-remodeling enzymes in the tumor niche. During the last several decades, scientific advances have increased the understanding of the complex interactions among cancer cells and tumor microenvironment components. Recently accumulated data have revealed the role of tumor microenvironment components in cancer development and progression, but also in treatment resistance. Moreover, the immunosuppressive tumor microenvironment interferes with the therapeutic results of currently available immunotherapy.

For this Special Issue of Biomedicines, we invite authors to submit contributions that provide new insights into the mechanisms of tumor microenvironment contribution to cancer development, progression, metastasis, immune escape, and therapy resistance. In particular, articles or reviews on new findings or concepts regarding the cellular and molecular interactions between tumor cells and microenvironment components, as well as their cooperation in tumor invasion and therapy resistance, are of great interest.

Dr. Adriana Grigoraș
Prof. Dr. Cornelia Amalinei
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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • tumor microenvironment
  • cancer-associated cells
  • extracellular matrix
  • cytokines and chemokines
  • angiogenesis
  • metastasis
  • invasion
  • therapy resistance

Published Papers (5 papers)

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Research

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23 pages, 25064 KiB  
Article
Intercellular Molecular Crosstalk Networks within Invasive and Immunosuppressive Tumor Microenvironment Subtypes Associated with Clinical Outcomes in Four Cancer Types
by Jinfen Wei, Wenqi Yu, Lei Wu, Zixi Chen, Guanda Huang, Meiling Hu and Hongli Du
Biomedicines 2023, 11(11), 3057; https://doi.org/10.3390/biomedicines11113057 - 14 Nov 2023
Viewed by 1335
Abstract
Heterogeneity is a critical basis for understanding how the tumor microenvironment (TME) contributes to tumor progression. However, an understanding of the specific characteristics and functions of TME subtypes (subTMEs) in the progression of cancer is required for further investigations into single-cell resolutions. Here, [...] Read more.
Heterogeneity is a critical basis for understanding how the tumor microenvironment (TME) contributes to tumor progression. However, an understanding of the specific characteristics and functions of TME subtypes (subTMEs) in the progression of cancer is required for further investigations into single-cell resolutions. Here, we analyzed single-cell RNA sequencing data of 250 clinical samples with more than 200,000 cells analyzed in each cancer datum. Based on the construction of an intercellular infiltration model and unsupervised clustering analysis, four, three, three, and four subTMEs were revealed in breast, colorectal, esophageal, and pancreatic cancer, respectively. Among the subTMEs, the immune-suppressive subTME (subTME-IS) and matrix remodeling with malignant cells subTME (subTME-MRM) were highly enriched in tumors, whereas the immune cell infiltration subTME (subTME-ICI) and precancerous state of epithelial cells subTME (subTME-PSE) were less in tumors, compared with paracancerous tissues. We detected and compared genes encoding cytokines, chemokines, cytotoxic mediators, PD1, and PD-L1. The results showed that these genes were specifically overexpressed in different cell types, and, compared with normal tissues, they were upregulated in tumor-derived cells. In addition, compared with other subTMEs, the expression levels of PDCD1 and TGFB1 were higher in subTME-IS. The Cox proportional risk regression model was further constructed to identify possible prognostic markers in each subTME across four cancer types. Cell-cell interaction analysis revealed the distinguishing features in molecular pairs among different subTMEs. Notably, ligand–receptor gene pairs, including COL1A1-SDC1, COL6A2-SDC1, COL6A3-SDC1, and COL4A1-ITGA2 between stromal and tumor cells, associated with tumor invasion phenotypes, poor patient prognoses, and tumor advanced progression, were revealed in subTME-MRM. C5AR1-RPS19, LGALS9-HAVCR2, and SPP1-PTGER4 between macrophages and CD8+ T cells, associated with CD8+ T-cell dysfunction, immunosuppressive status, and tumor advanced progression, were revealed in subTME-IS. The spatial co-location information of cellular and molecular interactions was further verified by spatial transcriptome data from colorectal cancer clinical samples. Overall, our study revealed the heterogeneity within the TME, highlighting the potential pro-invasion and pro-immunosuppressive functions and cellular infiltration characteristics of specific subTMEs, and also identified the key cellular and molecular interactions that might be associated with the survival, invasion, immune escape, and classification of cancer patients across four cancer types. Full article
(This article belongs to the Special Issue Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives)
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14 pages, 6727 KiB  
Article
Spheroids of FAP-Positive Cell Lines as a Model for Screening Drugs That Affect FAP Expression
by Victor V. Pleshkan, Marina V. Zinovyeva, Dina V. Antonova and Irina V. Alekseenko
Biomedicines 2023, 11(7), 2017; https://doi.org/10.3390/biomedicines11072017 - 18 Jul 2023
Viewed by 1615
Abstract
Fibroblast activation protein has a unique expression profile that manifests mainly in wounds and tumors, which anticipates it as an encouraging and selective target for anticancer therapy. However, research of the therapeutic potential of FAP is limited both by legal restraints when working [...] Read more.
Fibroblast activation protein has a unique expression profile that manifests mainly in wounds and tumors, which anticipates it as an encouraging and selective target for anticancer therapy. However, research of the therapeutic potential of FAP is limited both by legal restraints when working in vivo and by the difficulty of obtaining standardized primary cultures of FAP-positive cancer-associated fibroblasts due to their high heterogeneity. We found that 3D spheroids of FAP-positive cell lines could serve as robust and convenient models of FAP expression, in contrast to monolayers. By exposing such spheroids to various factors and compounds, it is possible to study changes in FAP expression, which are easily detected by confocal microscopy. FAP expression increases under the influence of the TGFβ, does not depend on pH, and decreases during hypoxia and starvation. We believe that the proposed model could be used to organize large-scale high-throughput screening of drugs that target FAP expression. Full article
(This article belongs to the Special Issue Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives)
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12 pages, 2348 KiB  
Article
The Significance of Matrix Metalloproteinase 9 (MMP-9) and Metalloproteinase 2 (MMP-2) in Urinary Bladder Cancer
by Jacek Kudelski, Anna Tokarzewicz, Monika Gudowska-Sawczuk, Barbara Mroczko, Piotr Chłosta, Marta Bruczko-Goralewska, Przemysław Mitura and Grzegorz Młynarczyk
Biomedicines 2023, 11(3), 956; https://doi.org/10.3390/biomedicines11030956 - 20 Mar 2023
Cited by 3 | Viewed by 1745
Abstract
Introduction: Urinary bladder cancer is a serious oncological problem that is the cause of many deaths worldwide. The processes of metastasis and origination of local tumor invasion depend on the extracellular matrix (ECM) degradation. The cancer microenvironment, particularly the ECM, may be considered [...] Read more.
Introduction: Urinary bladder cancer is a serious oncological problem that is the cause of many deaths worldwide. The processes of metastasis and origination of local tumor invasion depend on the extracellular matrix (ECM) degradation. The cancer microenvironment, particularly the ECM, may be considered a key factor in cancer progression. Matrix metalloproteinases (MMPs) are classified as the main factors responsible for the degradation of ECM components. Therefore, the aim of the study was to evaluate the expression and activity of matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9) in urinary bladder cancer according to different stages. Material and methods: Urinary bladder tissue samples were analyzed. Cancer patients were divided into two groups: low-grade tumors (LG; Group I) and high-grade tumors (HG; Group II). Control tissue was obtained from the opposite site to the tumor. MMPs content and activity (actual and specific) were evaluated using ELISA and Western blot methods, respectively. Results: Both MMPs are present in high and low molecular complexes in healthy or bladder cancer tissues. The content of MMP-9 is enhanced in comparison with MMP-2, particularly in HG cancer tissue. The actual activity of MMP-2 was highest in LG cancer tissue whereas the actual activity of MMP-9 was highest in HG cancer. Specific activity of both MMPs was highest in LG cancer, but the activity of MMP-9 was higher in comparison with MMP-2. Conclusions: In conclusion, the content and specific activity of MMP-9 were increased in comparison with MMP-2. The revealed differences in content and activity of both MMPs demonstrate their different participation in ECM remodeling at different stages of cancer development. Moreover, it seems that MMP-9 has higher clinical utility than MMP-2 as a potential therapeutic option and a diagnostic biomarker of urinary bladder cancer. Full article
(This article belongs to the Special Issue Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives)
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Review

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21 pages, 2371 KiB  
Review
Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer
by Adriana Grigoraș and Cornelia Amalinei
Biomedicines 2023, 11(9), 2401; https://doi.org/10.3390/biomedicines11092401 - 28 Aug 2023
Cited by 1 | Viewed by 1444
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed types of cancer, especially in obese patients, and the second cause of cancer-related death worldwide. Based on these data, extensive research has been performed over the last decades to decipher the pivotal role [...] Read more.
Colorectal cancer (CRC) is one of the most commonly diagnosed types of cancer, especially in obese patients, and the second cause of cancer-related death worldwide. Based on these data, extensive research has been performed over the last decades to decipher the pivotal role of the tumor microenvironment (TME) and its cellular and molecular components in CRC development and progression. In this regard, substantial progress has been made in the identification of cancer-associated adipocytes’ (CAAs) characteristics, considering their active role in the CCR tumor niche, by releasing a panel of metabolites, growth factors, and inflammatory adipokines, which assist the cancer cells’ development. Disposed in the tumor invasion front, CAAs exhibit a fibroblastic-like phenotype and establish a bidirectional molecular dialogue with colorectal tumor cells, which leads to functional changes in both cell types and contributes to tumor progression. CAAs also modulate the antitumor immune cells’ response and promote metabolic reprogramming and chemotherapeutic resistance in colon cancer cells. This review aims to report recent cumulative data regarding the molecular mechanisms of CAAs’ differentiation and their activity spectrum in the TME of CRC. A better understanding of CAAs and the molecular interplay between CAAs and tumor cells will provide insights into tumor biology and may open the perspective of new therapeutic opportunities in CRC patients. Full article
(This article belongs to the Special Issue Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives)
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19 pages, 9728 KiB  
Review
The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer
by Ali Mussa, Hafeez Abiola Afolabi, Nazmul Huda Syed, Mustafa Talib, Ahmad Hafiz Murtadha, Khalid Hajissa, Noor Fatmawati Mokhtar, Rohimah Mohamud and Rosline Hassan
Biomedicines 2023, 11(4), 1060; https://doi.org/10.3390/biomedicines11041060 - 30 Mar 2023
Cited by 3 | Viewed by 1981
Abstract
Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective [...] Read more.
Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective treatments for BC. The relationship between inflammation and tumorigenesis is well established, and the activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is frequently identified in BC. Constitutive NF-κB activation is linked to cell survival, metastasis, proliferation, and hormonal, chemo-, and radiotherapy resistance. Moreover, the crosstalk between NF-κB and other transcription factors is well documented. It is reported that vitamin C plays a key role in preventing and treating a number of pathological conditions, including cancer, when administered at remarkably high doses. Indeed, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli. In this review, we examine the various NF-κB impacts on BC development. We also provide some insight into how the NF-κB network may be targeted as a potential vulnerability by using natural pro-oxidant therapies such as vitamin C. Full article
(This article belongs to the Special Issue Tumor Microenvironment: From Cellular Components to Therapeutic Perspectives)
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