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Plasticity in Cancer and in Microenvironmental Cells

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

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 29920

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Special Issue Editor

Dr. Jozsef Dudas

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Guest Editor

Department of Otorhinolaryngology, Medical University of Innsbruck, Innsbruck, Austria
Interests: epithelial-to-mesenchymal transition; fibroblasts; chemokines; head and neck squamous cell carcinoma; curcumin; tumor progression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The plasticity of cancer tissue, which contains tumor cells, either of epithelial or mesenchymal origin, and stroma cells is a major hallmark that enables adaptation and resistance mechanisms, immune and therapy escapes, but might also contribute to successful therapy. The development of knowledge on tumor microenvironment, non-tumor cell-components effects on the support or inhibition of tumor growth, dependence and independence mechanisms of tumor cells on hormones, virus oncogenes, growth factors or driver mutations are some of the manifold dimensions of understanding of cancer tissue dynamics. This Special Issue will welcome original experimental or clinical research papers, comprehensive reviews, case reports, communications, and technical notes form any area of oncology, which attempts to contribute to the understanding of how a continuously changing interaction between tumor and stroma elements define and form the shape of cancer or allow options that enable tumor cells to escape treatment efforts. Changes in cancer cell genomes, cell population selection, conversion of bulk cancer cells to cancer stem cells, epithelial-to-mesenchymal transdifferentiation, polarization of macrophages, changes in populations of fibroblasts, myofibroblast activation, development of cancer-associated fibroblasts, functional reprogramming of microenvironmental cells, angiogenesis, and immune escape are only few examples of the numerous possibilities of how the cancer tissue adapts itself to actual conditions. Mechanical changes in the composition of the cancer microenvironment such as stiffness, the chemical constitution of cell-free environment, changes of pH, ion balance, conductivity, and equilibrium of active-, inactive-, mature-, and pro-enzymes are important and rarely discussed issues, which we would be happy to read about. We are also interested in articles about shifting between mitochondrial oxidative phosphorylation to glycolysis, hypoxia effects, unsaturated fatty acid effects. Clinical studies about related biomarkers, patient survival correlation factors and studies on tumor progression are also interesting for us. From the valuable contributions of authors to this issue, a considerate novel colorful view of the dynamic plastic nature of cancer tissue will be painted on our canvas.

Dr. Jozsef Dudas
Guest Editor

Manuscript Submission Information

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Keywords

tumor microenvironment
adhesion assays
xenografts
cancer models
extracellular matrix
tumor progression
patient survival
therapy outcome
plasticity
cancer stem cells
cancer-associated fibroblasts
cancer tissue metabolism
genomic instability
driver mutations
survival factors
senescence
apoptosis
mechanical barriers
matrix degradation
orospheres
exosomes
epithelial-to-mesenchymal transdifferentiation
virus oncogenes
tissue slice culture

Published Papers (5 papers)

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Research

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16 pages, 1701 KiB

Open AccessArticle

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

by Maria Lucia Hirata Katayama, René Aloísio da Costa Vieira, Victor Piana Andrade, Rosimeire Aparecida Roela, Luiz Guilherme Cernaglia Aureliano Lima, Ligia Maria Kerr, Adriano Polpo de Campos, Carlos Alberto de Bragança Pereira, Pedro Adolpho de Menezes Pacheco Serio, Giselly Encinas, Simone Maistro, Matheus de Almeida Leite Petroni, Maria Mitzi Brentani and Maria Aparecida Azevedo Koike Folgueira

Cells 2019, 8(12), 1566; https://doi.org/10.3390/cells8121566 - 4 Dec 2019

Cited by 24 | Viewed by 4038

Abstract

Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response. Full article

(This article belongs to the Special Issue Plasticity in Cancer and in Microenvironmental Cells)

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25 pages, 13263 KiB

Open AccessArticle

Development of a Stromal Microenvironment Experimental Model Containing Proto-Myofibroblast Like Cells and Analysis of Its Crosstalk with Melanoma Cells: A New Tool to Potentiate and Stabilize Tumor Suppressor Phenotype of Dermal Myofibroblasts

by Angelica Avagliano, Maria Rosaria Ruocco, Rosarita Nasso, Federica Aliotta, Gennaro Sanità, Antonino Iaccarino, Claudio Bellevicine, Gaetano Calì, Giuseppe Fiume, Stefania Masone, Mariorosario Masullo, Stefania Montagnani and Alessandro Arcucci

Cells 2019, 8(11), 1435; https://doi.org/10.3390/cells8111435 - 14 Nov 2019

Cited by 15 | Viewed by 4197

Abstract

Melanoma is one of the most aggressive solid tumors and includes a stromal microenvironment that regulates cancer growth and progression. The components of stromal microenvironment such as fibroblasts, fibroblast aggregates and cancer-associated fibroblasts (CAFs) can differently influence the melanoma growth during its distinct stages. In this work, we have developed and studied a stromal microenvironment model, represented by fibroblasts, proto-myofibroblasts, myofibroblasts and aggregates of inactivated myofibroblasts, such as spheroids. In particular, we have generated proto-myofibroblasts from primary cutaneous myofibroblasts. The phenotype of proto-myofibroblasts is characterized by a dramatic reduction of α-smooth muscle actin (α-SMA) and cyclooxygenase-2 (COX-2) protein levels, as well as an enhancement of cell viability and migratory capability compared with myofibroblasts. Furthermore, proto-myofibroblasts display the mesenchymal marker vimentin and less developed stress fibers, with respect to myofibroblasts. The analysis of crosstalk between the stromal microenvironment and A375 or A2058 melanoma cells has shown that the conditioned medium of proto-myofibroblasts is cytotoxic, mainly for A2058 cells, and dramatically reduces the migratory capability of both cell lines compared with the melanoma-control conditioned medium. An array analysis of proto-myofibroblast and melanoma cell-conditioned media suggests that lower levels of some cytokines and growth factors in the conditioned medium of proto-myofibroblasts could be associated with their anti-tumor activity. Conversely, the conditioned media of melanoma cells do not influence the cell viability, outgrowth, and migration of proto-myofibroblasts from spheroids. Interestingly, the conditioned medium of proto-myofibroblasts does not alter the cell viability of both BJ-5ta fibroblast cells and myofibroblasts. Hence, proto-myofibroblasts could be useful in the study of new therapeutic strategies targeting melanoma. Full article

(This article belongs to the Special Issue Plasticity in Cancer and in Microenvironmental Cells)

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15 pages, 1595 KiB

Open AccessArticle

Genes Controlled by DNA Methylation Are Involved in Wilms Tumor Progression

by João Victor da Silva Guerra, Bruna Maria de Sá Pereira, Jéssica Gonçalves Vieira da Cruz, Nicole de Miranda Scherer, Carolina Furtado, Rafaela Montalvão de Azevedo, Paulo Sergio Lopes de Oliveira, Paulo Faria, Mariana Boroni, Beatriz de Camargo and Mariana Maschietto

Cells 2019, 8(8), 921; https://doi.org/10.3390/cells8080921 - 17 Aug 2019

Cited by 12 | Viewed by 5933

Abstract

To identify underlying mechanisms involved with metastasis formation in Wilms tumors (WTs), we performed comprehensive DNA methylation and gene expression analyses of matched normal kidney (NK), WT blastemal component, and metastatic tissues (MT) from patients treated under SIOP 2001 protocol. A linear Bayesian framework model identified 497 differentially methylated positions (DMPs) between groups that discriminated NK from WT, but MT samples were divided in two groups. Accordingly, methylation variance grouped NK and three MT samples tightly together and all WT with four MT samples that showed high variability. WT were hypomethylated compared to NK, and MT had a hypermethylated pattern compared to both groups. The methylation patterns were in agreement with methylases and demethylases expression. Methylation data pointed to the existence of two groups of metastases. While hierarchical clustering analysis based on the expression of all 2569 differentially expressed genes (DEGs) discriminated WT and MT from all NK samples, the hierarchical clustering based on the expression of 44 genes with a differentially methylated region (DMR) located in their promoter region revealed two groups: one containing all NKs and three MTs and one containing all WT and four MTs. Methylation changes might be controlling expression of genes associated with WT progression. The 44 genes are candidates to be further explored as a signature for metastasis formation in WT. Full article

(This article belongs to the Special Issue Plasticity in Cancer and in Microenvironmental Cells)

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Review

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15 pages, 1094 KiB

Open AccessReview

Blood and Cancer: Cancer Stem Cells as Origin of Hematopoietic Cells in Solid Tumor Microenvironments

by Ghmkin Hassan and Masaharu Seno

Cells 2020, 9(5), 1293; https://doi.org/10.3390/cells9051293 - 22 May 2020

Cited by 18 | Viewed by 7976

Abstract

The concepts of hematopoiesis and the generation of blood and immune cells from hematopoietic stem cells are some steady concepts in the field of hematology. However, the knowledge of hematopoietic cells arising from solid tumor cancer stem cells is novel. In the solid tumor microenvironment, hematopoietic cells play pivotal roles in tumor growth and progression. Recent studies have reported that solid tumor cancer cells or cancer stem cells could differentiate into hematopoietic cells. Here, we discuss efforts and research that focused on the presence of hematopoietic cells in tumor microenvironments. We also discuss hematopoiesis from solid tumor cancer stem cells and clarify the notion of differentiation of solid tumor cancer stem cells into non-cancer hematopoietic stem cells. Full article

(This article belongs to the Special Issue Plasticity in Cancer and in Microenvironmental Cells)

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25 pages, 7454 KiB

Open AccessReview

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

by József Dudás, Andrea Ladányi, Julia Ingruber, Teresa Bernadette Steinbichler and Herbert Riechelmann

Cells 2020, 9(2), 428; https://doi.org/10.3390/cells9020428 - 12 Feb 2020

Cited by 114 | Viewed by 7138

Abstract

Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8⁺ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use. Full article

(This article belongs to the Special Issue Plasticity in Cancer and in Microenvironmental Cells)

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