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Cells
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The Crosstalk between Malignant Cells and Their Microenvironment
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The Crosstalk between Malignant Cells and Their Microenvironment

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

Deadline for manuscript submissions: closed (15 November 2024) | Viewed by 14699

Special Issue Editor

Dr. Silvia Peppicelli

E-Mail Website
Guest Editor
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
Interests: tumor microenvironment; melanoma progression; cancer stem cells; tumor acidosis; tumor metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The tumor microenvironment (TME) is a complex and dynamic system which plays a key role in cancer development and progression. In addition to malignant cells, the TME consists of stromal cells, cells of the immune system, blood and lymphatic vasculature, and extracellular matrix proteins. These TME components communicate with each other through continuous direct and indirect interactions, thanks to a complex network of cytokines, chemokines, and secreted growth factors, as well as pro-inflammatory factors and matrix remodeling enzymes, which lead to TME modifications and help cancer cells survive in these harsh microenvironment. Indeed, due to the dysregulated proliferation of tumor cells, altered cancer metabolism, and chaotic tumor blood vessels, the TME is often characterized by hypoxia and acidosis. To adapt to this environment, cancer cells need to change their phenotype, increasing their aggressiveness and resistance and reprogramming their metabolism. Both the interaction between tumor cells and the acid/hypoxic microenvironment, and the cross-talk between tumor cells and the various normal resident cells present in tumor tissues, modulate cancer cell behavior in the primary and the metastatic cancer lesion, inducing the epithelial–mesenchymal transition (EMT) process,  resistance to apoptosis, and stem-like features, for example. Moreover, to satisfy their need in energy, tumor cells became capable of using metabolites present in the microenvironment, taking advantage of the cross-talk with stromal cells and capturing extracellular vesicles released by the neighboring cells. 

This Special Issue aims to examine interaction mechanisms between the tumor and their microenvironment to understand the role of different TME components in cancer initiation, progression, metastasization, immune escape, and therapeutic resistance. Highlighting new mechanisms of interaction between TME components  can open new therapeutic perspectives for the treatment of cancer.

Dr. Silvia Peppicelli
Guest Editor

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Keywords

  • tumor microenvironment
  • tumor hypoxia
  • extracellular acidosis
  • angiogenesis
  • stromal cells
  • immune cells
  • extracellular vescicles
  • extracellular matrix

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Published Papers (6 papers)

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Research

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18 pages, 6893 KiB  
Article
Can Galectin-3 Be a Novel Biomarker in Chronic Lymphocytic Leukemia?
by Justyna Woś, Agata Szymańska, Natalia Lehman, Sylwia Chocholska, Michał Zarobkiewicz, Piotr Pożarowski and Agnieszka Bojarska-Junak
Cells 2024, 13(1), 30; https://doi.org/10.3390/cells13010030 - 22 Dec 2023
Cited by 1 | Viewed by 1730
Abstract
Galectin-3’s (Gal-3) effect on the pathogenesis of chronic lymphocytic leukemia (CLL) has not yet been extensively studied. The present study aims to analyze the potential role of Gal-3 as a prognostic biomarker in CLL patients. The Gal-3 expression was evaluated in CLL cells [...] Read more.
Galectin-3’s (Gal-3) effect on the pathogenesis of chronic lymphocytic leukemia (CLL) has not yet been extensively studied. The present study aims to analyze the potential role of Gal-3 as a prognostic biomarker in CLL patients. The Gal-3 expression was evaluated in CLL cells with RT-qPCR and flow cytometry. Due to the unclear clinical significance of soluble Gal-3 in CLL, our goal was also to assess the prognostic value of Gal-3 plasma level. Because cell survival is significantly affected by the interaction between Gal-3 and proteins such as Bcl-2, the results of Gal-3 expression analysis were also compared with the expression of Bcl-2. The results were analyzed for known prognostic factors, clinical data, and endpoints such as time to first treatment and overall survival time. Our research confirmed that Gal-3 is detected in and on CLL cells. However, using Gal-3 as a potential biomarker in CLL is challenging due to the significant heterogeneity in its expression in CLL cells. Moreover, our results revealed that Gal-3 mRNA expression in leukemic B cells is associated with the expression of proliferation markers (Ki-67 and PCNA) as well as anti-apoptotic protein Bcl-2 and can play an important role in supporting CLL cells. Full article
(This article belongs to the Special Issue The Crosstalk between Malignant Cells and Their Microenvironment)
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20 pages, 8719 KiB  
Article
Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts
by Elena Andreucci, Bianca Saveria Fioretto, Irene Rosa, Marco Matucci-Cerinic, Alessio Biagioni, Eloisa Romano, Lido Calorini and Mirko Manetti
Cells 2023, 12(6), 939; https://doi.org/10.3390/cells12060939 - 20 Mar 2023
Cited by 9 | Viewed by 2811
Abstract
Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of [...] Read more.
Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy. Full article
(This article belongs to the Special Issue The Crosstalk between Malignant Cells and Their Microenvironment)
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25 pages, 7610 KiB  
Article
The Characteristics of Tumor Microenvironment Predict Survival and Response to Immunotherapy in Adrenocortical Carcinomas
by Guichuan Lai, Hui Liu, Jielian Deng, Kangjie Li, Cong Zhang, Xiaoni Zhong and Biao Xie
Cells 2023, 12(5), 755; https://doi.org/10.3390/cells12050755 - 27 Feb 2023
Cited by 5 | Viewed by 2584
Abstract
Increasing evidence confirms that tumor microenvironment (TME) can influence tumor progression and treatment, but TME is still understudied in adrenocortical carcinoma (ACC). In this study, we first scored TME using the xCell algorithm, then defined genes associated with TME, and then used consensus [...] Read more.
Increasing evidence confirms that tumor microenvironment (TME) can influence tumor progression and treatment, but TME is still understudied in adrenocortical carcinoma (ACC). In this study, we first scored TME using the xCell algorithm, then defined genes associated with TME, and then used consensus unsupervised clustering analysis to construct TME-related subtypes. Meanwhile, weighted gene co-expression network analysis was used to identify modules correlated with TME-related subtypes. Ultimately, the LASSO-Cox approach was used to establish a TME-related signature. The results showed that TME-related scores in ACC may not correlate with clinical features but do promote a better overall survival. Patients were classified into two TME-related subtypes. Subtype 2 had more immune signaling features, higher expression of immune checkpoints and MHC molecules, no CTNNB1 mutations, higher infiltration of macrophages and endothelial cells, lower tumor immune dysfunction and exclusion scores, and higher immunophenoscore, suggesting that subtype 2 may be more sensitive to immunotherapy. 231 modular genes highly relevant to TME-related subtypes were identified, and a 7-gene TME-related signature that independently predicted patient prognosis was established. Our study revealed an integrated role of TME in ACC and helped to identify those patients who really responded to immunotherapy, while providing new strategies on risk management and prognosis prediction. Full article
(This article belongs to the Special Issue The Crosstalk between Malignant Cells and Their Microenvironment)
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Review

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32 pages, 1008 KiB  
Review
Extracellular Matrix as a Target in Melanoma Therapy: From Hypothesis to Clinical Trials
by Yuriy P. Mayasin, Maria N. Osinnikova, Chulpan B. Kharisova, Kristina V. Kitaeva, Ivan Y. Filin, Anna V. Gorodilova, Grigorii I. Kutovoi, Valeriya V. Solovyeva, Anatolii I. Golubev and Albert A. Rizvanov
Cells 2024, 13(22), 1917; https://doi.org/10.3390/cells13221917 - 19 Nov 2024
Viewed by 450
Abstract
Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell–ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, [...] Read more.
Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell–ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting. Full article
(This article belongs to the Special Issue The Crosstalk between Malignant Cells and Their Microenvironment)
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30 pages, 4336 KiB  
Review
Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles
by Artem Ten, Vadim Kumeiko, Vladislav Farniev, Huile Gao and Maxim Shevtsov
Cells 2024, 13(8), 682; https://doi.org/10.3390/cells13080682 - 15 Apr 2024
Cited by 3 | Viewed by 3343
Abstract
The tumor microenvironment (TME) plays an important role in the process of tumorigenesis, regulating the growth, metabolism, proliferation, and invasion of cancer cells, as well as contributing to tumor resistance to the conventional chemoradiotherapies. Several types of cells with relatively stable phenotypes have [...] Read more.
The tumor microenvironment (TME) plays an important role in the process of tumorigenesis, regulating the growth, metabolism, proliferation, and invasion of cancer cells, as well as contributing to tumor resistance to the conventional chemoradiotherapies. Several types of cells with relatively stable phenotypes have been identified within the TME, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), neutrophils, and natural killer (NK) cells, which have been shown to modulate cancer cell proliferation, metastasis, and interaction with the immune system, thus promoting tumor heterogeneity. Growing evidence suggests that tumor-cell-derived extracellular vesicles (EVs), via the transfer of various molecules (e.g., RNA, proteins, peptides, and lipids), play a pivotal role in the transformation of normal cells in the TME into their tumor-associated protumorigenic counterparts. This review article focuses on the functions of EVs in the modulation of the TME with a view to how exosomes contribute to the transformation of normal cells, as well as their importance for cancer diagnosis and therapy. Full article
(This article belongs to the Special Issue The Crosstalk between Malignant Cells and Their Microenvironment)
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18 pages, 1161 KiB  
Review
Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma
by Irene Fiorilla, Simona Martinotti, Alberto Maria Todesco, Gregorio Bonsignore, Maria Cavaletto, Mauro Patrone, Elia Ranzato and Valentina Audrito
Cells 2023, 12(16), 2048; https://doi.org/10.3390/cells12162048 - 11 Aug 2023
Cited by 8 | Viewed by 2733
Abstract
Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, [...] Read more.
Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, and persistent aberrant signaling. Together, these processes, over the years, force normal mesothelial cells’ transformation. Chronic inflammation supported by “frustrated” macrophages exposed to asbestos fibers is also boosted by the release of pro-inflammatory cytokines, chemokines, growth factors, damage-associated molecular proteins (DAMPs), and the generation of ROS. In addition, the hypoxic microenvironment influences MPM and immune cells’ features, leading to a significant rewiring of metabolism and phenotypic plasticity, thereby supporting tumor aggressiveness and modulating infiltrating immune cell responses. This review provides an overview of the complex tumor–host interactions within the MPM tumor microenvironment at different levels, i.e., soluble factors, metabolic crosstalk, and oxidative stress, and explains how these players supporting tumor transformation and progression may become potential and novel therapeutic targets in MPM. Full article
(This article belongs to the Special Issue The Crosstalk between Malignant Cells and Their Microenvironment)
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