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Cancers
Special Issues
Intra-tumoral Heterogeneity—Experimental Models, Molecular Mechanisms and Clinical Relevance
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Intra-tumoral Heterogeneity—Experimental Models, Molecular Mechanisms and Clinical Relevance

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 10989

Special Issue Editor

Prof. Dr. Raymond Lai

E-Mail Website
Guest Editor
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 1Z2, Canada
Interests: autophagy; cancer plasticity and stemness; chemoresistance; intratumoral heterogeneity; lymphoma; myc; oncogenic tyrosine kinases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Intratumoral heterogeneity (ITH) has increasingly been recognized as a key contributing factor to chemoresistance and cancer relapse. Thus, improved understanding of the molecular mechanisms underlying ITH is highly important and relevant in the quest against cancers. ITH can be generally categorized into two groups, namely, clonal and nonclonal. Clonal ITH, which is linked to the intrinsic genetic instability of cancer cells, is characterized by the accumulation of genetic and epigenetic aberrations that commonly accompany tumor progression. Nonclonal ITH, which is closely linked to the interactions between cancer cells and microenvironment, is characterized by phenotypic plasticity. One of the most characterized mechanisms to generate nonclonal ITH is epithelial–mesenchymal transition, in which relatively mature-appearing epithelial cells de-differentiate into immature-appearing, stem-like mesenchymal cells. Chemotherapeutic agents and various hostile microenvironments (e.g., hypoxia and oxidative stress) are known to promote this type of phenotypic conversion, which is often associated with increased chemoresistance. Using tumor samples from patients, studies have found a significant correlation between the acquisition of stem-like features in cancer cells and a worse clinical outcome. In recent years, various technical advances have greatly facilitated the detection and molecular characterization of ITH, such as the use of next-generation sequencing of single cells, CRISPR barcoding, and various transcription factor reporter systems. Both research and review articles pertaining to these topics are welcome. 

Prof. Dr. Raymond Lai
Guest Editor

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Published Papers (3 papers)

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Research

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22 pages, 22640 KiB  
Article
Analysis of the Single-Cell Heterogeneity of Adenocarcinoma Cell Lines and the Investigation of Intratumor Heterogeneity Reveals the Expression of Transmembrane Protein 45A (TMEM45A) in Lung Adenocarcinoma Cancer Patients
by Patrícia Neuperger, József Á. Balog, László Tiszlavicz, József Furák, Nikolett Gémes, Edit Kotogány, Klára Szalontai, László G. Puskás and Gábor J. Szebeni
Cancers 2022, 14(1), 144; https://doi.org/10.3390/cancers14010144 - 29 Dec 2021
Cited by 13 | Viewed by 4086
Abstract
Intratumoral heterogeneity (ITH) is responsible for the majority of difficulties encountered in the treatment of lung-cancer patients. Therefore, the heterogeneity of NSCLC cell lines and primary lung adenocarcinoma was investigated by single-cell mass cytometry (CyTOF). First, we studied the single-cell heterogeneity of frequent [...] Read more.
Intratumoral heterogeneity (ITH) is responsible for the majority of difficulties encountered in the treatment of lung-cancer patients. Therefore, the heterogeneity of NSCLC cell lines and primary lung adenocarcinoma was investigated by single-cell mass cytometry (CyTOF). First, we studied the single-cell heterogeneity of frequent NSCLC adenocarcinoma models, such as A549, H1975, and H1650. The intra- and inter-cell-line single-cell heterogeneity is represented in the expression patterns of 13 markers—namely GLUT1, MCT4, CA9, TMEM45A, CD66, CD274 (PD-L1), CD24, CD326 (EpCAM), pan-keratin, TRA-1-60, galectin-3, galectin-1, and EGFR. The qRT-PCR and CyTOF analyses revealed that a hypoxic microenvironment and altered metabolism may influence cell-line heterogeneity. Additionally, human primary lung adenocarcinoma and non-involved healthy lung tissue biopsies were homogenized to prepare a single-cell suspension for CyTOF analysis. The CyTOF showed the ITH of human primary lung adenocarcinoma for 14 markers; particularly, the higher expressions of GLUT1, MCT4, CA9, TMEM45A, and CD66 were associated with the lung-tumor tissue. Our single-cell results are the first to demonstrate TMEM45A expression in human lung adenocarcinoma, which was verified by immunohistochemistry. Full article
(This article belongs to the Special Issue Intra-tumoral Heterogeneity—Experimental Models, Molecular Mechanisms and Clinical Relevance)
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12 pages, 20971 KiB  
Article
Development of a Novel Weighted Ranking Method for Immunohistochemical Quantification of a Heterogeneously Expressed Protein in Gastro-Esophageal Cancers
by Cathy E. Richards, Katherine M. Sheehan, Elaine W. Kay, Charlotta Hedner, David Borg, Joanna Fay, Anthony O’Grady, Arnold D. K. Hill, Karin Jirström and Ann M. Hopkins
Cancers 2021, 13(6), 1286; https://doi.org/10.3390/cancers13061286 - 13 Mar 2021
Cited by 1 | Viewed by 2005
Abstract
High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development [...] Read more.
High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically significant correlations between JAM-A/HER2 expression. Given the growing importance of immunohistochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients. Full article
(This article belongs to the Special Issue Intra-tumoral Heterogeneity—Experimental Models, Molecular Mechanisms and Clinical Relevance)
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Review

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31 pages, 3003 KiB  
Review
Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma
by Tiziana Servidei, Donatella Lucchetti, Pierluigi Navarra, Alessandro Sgambato, Riccardo Riccardi and Antonio Ruggiero
Cancers 2021, 13(23), 6100; https://doi.org/10.3390/cancers13236100 - 3 Dec 2021
Cited by 6 | Viewed by 3970
Abstract
Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer [...] Read more.
Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy. Full article
(This article belongs to the Special Issue Intra-tumoral Heterogeneity—Experimental Models, Molecular Mechanisms and Clinical Relevance)
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