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Cancers
Special Issues
Metastatic Progression and Tumour Heterogeneity
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Metastatic Progression and Tumour Heterogeneity

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 August 2019) | Viewed by 107837

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Fred Hollande

E-Mail Website
Guest Editor
Department of Clinical Pathology, University of Melbourne, Parkville, VIC 3010, Australia
Interests: gastro-intestinal cancers; tumor progression; metastasis; treatment response; tumor heterogeneity; cell adhesion; cell signaling
Dr. Delphine Merino

E-Mail Website
Guest Editor
Translational Breast Cancer Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
Interests: breast cancer; metastasis; cell death; tumor progression; heterogeneity

Special Issue Information

Dear Colleagues,

Intratumoral heterogeneity is one of the biggest current challenges for cancer therapy. However, exciting recent developments in single-cell -omics, cellular tracking, and imaging, alongside the expansion of new tools to study clonal and phenotypic diversity in patient samples—such as PDXs, organoids, and liquid biopsies—enable a deeper understanding of the heterogeneous molecular mechanisms that drive tumor progression and underlie poor treatment outcomes.

These new research approaches have unraveled an unforeseen level of cellular and molecular complexity within tumors. High-throughput sequencing has highlighted the broad inter- and intra-tumoral heterogeneity that exists amongst patient cohorts and across tumor streams, while longitudinal studies indicate that the diversity of malignant cell populations that make up primary tumors and metastases can evolve in space and time. Cancer therapies can also reshape the cellular and molecular profile of tumors, and the elucidation of the mechanisms that drive treatment-induced plasticity, selection, and resistance will inform the design of new combinational therapies.

Furthermore, the cellular and molecular features of the tumor microenvironment, including immune cells, have to be taken into consideration for the understanding of tumor progression. Targeting both tumor cells and tumor microenvironment is also an exciting area of investigation, with new approaches such as immunotherapy now emerging as powerful treatment alternatives. Importantly, the heterogeneity of microenvironmental effectors and signals is still marginally understood and will undoubtedly represent the focus of extensive analyses in the next few years.

Thus, comprehensive and integrated analyses of tumor and microenvironment heterogeneity are essential to both improve the overall diagnosis and treatment of patients with cancer and further progress towards precision medicine. This Special Issue will highlight the state-of-the-art technologies aiming to dissect the heterogeneity of malignant cells and their microenvironment and will cover some of the promising discoveries that are likely to improve cancer patients’ outcome.

Assoc. Prof. Fred Hollande
Dr. Delphine Merino
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. 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.

Keywords

  • Tumor Progression
  • Heterogeneity
  • Cancer Therapy
  • Biopsies
  • Microenvironment

Published Papers (15 papers)

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Review

21 pages, 3352 KiB  
Review
Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer
by Jamie R. Kutasovic, Amy E. McCart Reed, Anna Sokolova, Sunil R. Lakhani and Peter T. Simpson
Cancers 2020, 12(4), 848; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040848 - 31 Mar 2020
Cited by 13 | Viewed by 3854
Abstract
Breast cancer is a remarkably complex and diverse disease. Subtyping based on morphology, genomics, biomarkers and/or clinical parameters seeks to stratify optimal approaches for management, but it is clear that every breast cancer is fundamentally unique. Intra-tumour heterogeneity adds further complexity and impacts [...] Read more.
Breast cancer is a remarkably complex and diverse disease. Subtyping based on morphology, genomics, biomarkers and/or clinical parameters seeks to stratify optimal approaches for management, but it is clear that every breast cancer is fundamentally unique. Intra-tumour heterogeneity adds further complexity and impacts a patient’s response to neoadjuvant or adjuvant therapy. Here, we review some established and more recent evidence related to the complex nature of breast cancer evolution. We describe morphologic and genomic diversity as it arises spontaneously during the early stages of tumour evolution, and also in the context of treatment where the changing subclonal architecture of a tumour is driven by the inherent adaptability of tumour cells to evolve and resist the selective pressures of therapy. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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32 pages, 1168 KiB  
Review
Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease
by James H. Monkman, Erik W. Thompson and Shivashankar H. Nagaraj
Cancers 2019, 11(11), 1745; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111745 - 07 Nov 2019
Cited by 7 | Viewed by 2808
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic [...] Read more.
Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic disease in order to identify actionable vulnerabilities. One such proposed vulnerability is epithelial mesenchymal plasticity (EMP), a process whereby neoplastic epithelial cells delaminate from their neighbours, either collectively or individually, allowing for their subsequent invasion into host tissue. This disruption of tissue homeostasis, particularly in PDAC, further promotes cellular transformation by inducing inflammatory interactions with the stromal compartment, which in turn contributes to intratumoural heterogeneity. This review describes the role of EMP in PDAC, and the preclinical target discovery that has been conducted to identify the molecular regulators and effectors of this EMP program. While inhibition of individual targets may provide therapeutic insights, a single ‘master-key’ remains elusive, making their collective interactions of greater importance in controlling the behaviours’ of heterogeneous tumour cell populations. Much work has been undertaken to understand key transcriptional programs that drive EMP in certain contexts, however, a collaborative appreciation for the subtle, context-dependent programs governing EMP regulation is needed in order to design therapeutic strategies to curb PDAC mortality. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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22 pages, 905 KiB  
Review
Single-Cell Analysis of Circulating Tumor Cells: Why Heterogeneity Matters
by Su Bin Lim, Chwee Teck Lim and Wan-Teck Lim
Cancers 2019, 11(10), 1595; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101595 - 19 Oct 2019
Cited by 57 | Viewed by 6876
Abstract
Unlike bulk-cell analysis, single-cell approaches have the advantage of assessing cellular heterogeneity that governs key aspects of tumor biology. Yet, their applications to circulating tumor cells (CTCs) are relatively limited, due mainly to the technical challenges resulting from extreme rarity of CTCs. Nevertheless, [...] Read more.
Unlike bulk-cell analysis, single-cell approaches have the advantage of assessing cellular heterogeneity that governs key aspects of tumor biology. Yet, their applications to circulating tumor cells (CTCs) are relatively limited, due mainly to the technical challenges resulting from extreme rarity of CTCs. Nevertheless, recent advances in microfluidics and immunoaffinity enrichment technologies along with sequencing platforms have fueled studies aiming to enrich, isolate, and sequence whole genomes of CTCs with high fidelity across various malignancies. Here, we review recent single-cell CTC (scCTC) sequencing efforts, and the integrated workflows, that have successfully characterized patient-derived CTCs. We examine how these studies uncover DNA alterations occurring at multiple molecular levels ranging from point mutations to chromosomal rearrangements from a single CTC, and discuss their cellular heterogeneity and clinical consequences. Finally, we highlight emerging strategies to address key challenges currently limiting the translation of these findings to clinical practice. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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22 pages, 2836 KiB  
Review
The Complexities of Metastasis
by Beatriz P. San Juan, Maria J. Garcia-Leon, Laura Rangel, Jacky G. Goetz and Christine L. Chaffer
Cancers 2019, 11(10), 1575; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101575 - 16 Oct 2019
Cited by 26 | Viewed by 5684
Abstract
Therapies that prevent metastatic dissemination and tumor growth in secondary organs are severely lacking. A better understanding of the mechanisms that drive metastasis will lead to improved therapies that increase patient survival. Within a tumor, cancer cells are equipped with different phenotypic and [...] Read more.
Therapies that prevent metastatic dissemination and tumor growth in secondary organs are severely lacking. A better understanding of the mechanisms that drive metastasis will lead to improved therapies that increase patient survival. Within a tumor, cancer cells are equipped with different phenotypic and functional capacities that can impact their ability to complete the metastatic cascade. That phenotypic heterogeneity can be derived from a combination of factors, in which the genetic make-up, interaction with the environment, and ability of cells to adapt to evolving microenvironments and mechanical forces play a major role. In this review, we discuss the specific properties of those cancer cell subgroups and the mechanisms that confer or restrict their capacity to metastasize. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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25 pages, 4849 KiB  
Review
Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer
by Camille Evrard, Gaëlle Tachon, Violaine Randrian, Lucie Karayan-Tapon and David Tougeron
Cancers 2019, 11(10), 1567; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101567 - 15 Oct 2019
Cited by 110 | Viewed by 11692
Abstract
Tumor DNA mismatch repair (MMR) deficiency testing is important to the identification of Lynch syndrome and decision making regarding adjuvant chemotherapy in stage II colorectal cancer (CRC) and has become an indispensable test in metastatic tumors due to the high efficacy of immune [...] Read more.
Tumor DNA mismatch repair (MMR) deficiency testing is important to the identification of Lynch syndrome and decision making regarding adjuvant chemotherapy in stage II colorectal cancer (CRC) and has become an indispensable test in metastatic tumors due to the high efficacy of immune checkpoint inhibitor (ICI) in deficient MMR (dMMR) tumors. CRCs greatly benefit from this testing as approximately 15% of them are dMMR but only 3% to 5% are at a metastatic stage. MMR status can be determined by two different methods, microsatellite instability (MSI) testing on tumor DNA, and immunohistochemistry of the MMR proteins on tumor tissue. Recent studies have reported a rate of 3% to 10% of discordance between these two tests. Moreover, some reports suggest possible intra- and inter-tumoral heterogeneity of MMR and MSI status. These issues are important to know and to clarify in order to define therapeutic strategy in CRC. This review aims to detail the standard techniques used for the determination of MMR and MSI status, along with their advantages and limits. We review the discordances that may arise between these two tests, tumor heterogeneity of MMR and MSI status, and possible explanations. We also discuss the strategies designed to distinguish sporadic versus germline dMMR/MSI CRC. Finally, we present new and accurate methods aimed at determining MMR/MSI status. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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16 pages, 1172 KiB  
Review
Tumor Endothelial Heterogeneity in Cancer Progression
by Nako Maishi, Dorcas A. Annan, Hiroshi Kikuchi, Yasuhiro Hida and Kyoko Hida
Cancers 2019, 11(10), 1511; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101511 - 09 Oct 2019
Cited by 64 | Viewed by 6312
Abstract
Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the [...] Read more.
Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the inner surfaces of tumor blood vessels reportedly show phenotypes distinct from those of their normal counterparts. As examples, TECs show cytogenetic abnormalities, resistance to anticancer drugs, activated proliferation and migration, and specific gene expression patterns. TECs contain stem-like cell populations, which means that the origin of TECs is heterogeneous. In addition, since some abnormal phenotypes in TECs are induced by factors in the tumor microenvironment, such as hypoxia and tumor cell-derived factors, phenotypic diversity in TECs may be caused in part by intratumoral heterogeneity. Recent studies have identified that the interaction of tumor cells and TECs by juxtacrine and paracrine signaling contributes to tumor malignancy. Understanding TEC abnormality and heterogeneity is important for treatment of cancers. This review provides an overview of the diversity of TECs and discusses the interaction between TECs and tumor cells in the tumor microenvironment. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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19 pages, 1734 KiB  
Review
Unraveling Heterogeneity in Epithelial Cell Fates of the Mammary Gland and Breast Cancer
by Alexandr Samocha, Hanna Doh, Kai Kessenbrock and Jeroen P. Roose
Cancers 2019, 11(10), 1423; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101423 - 24 Sep 2019
Cited by 4 | Viewed by 6238
Abstract
Fluidity in cell fate or heterogeneity in cell identity is an interesting cell biological phenomenon, which at the same time poses a significant obstacle for cancer therapy. The mammary gland seems a relatively straightforward organ with stromal cells and basal- and luminal- epithelial [...] Read more.
Fluidity in cell fate or heterogeneity in cell identity is an interesting cell biological phenomenon, which at the same time poses a significant obstacle for cancer therapy. The mammary gland seems a relatively straightforward organ with stromal cells and basal- and luminal- epithelial cell types. In reality, the epithelial cell fates are much more complex and heterogeneous, which is the topic of this review. Part of the complexity comes from the dynamic nature of this organ: the primitive epithelial tree undergoes extensively remodeling and expansion during puberty, pregnancy, and lactation and, unlike most other organs, the bulk of mammary gland development occurs late, during puberty. An active cell biological debate has focused on lineage commitment to basal- and luminal- epithelial cell fates by epithelial progenitor and stem cells; processes that are also relevant to cancer biology. In this review, we discuss the current understanding of heterogeneity in mammary gland and recent insights obtained through lineage tracing, signaling assays, and organoid cultures. Lastly, we relate these insights to cancer and ongoing efforts to resolve heterogeneity in breast cancer with single-cell RNAseq approaches. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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15 pages, 725 KiB  
Review
The Immune Microenvironment of Breast Cancer Progression
by Helen Tower, Meagan Ruppert and Kara Britt
Cancers 2019, 11(9), 1375; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091375 - 16 Sep 2019
Cited by 63 | Viewed by 17009
Abstract
Inflammation is now recognized as a hallmark of cancer. Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire. Once inside the tumour, the immune cells secrete [...] Read more.
Inflammation is now recognized as a hallmark of cancer. Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire. Once inside the tumour, the immune cells secrete cytokines that kick-start angiogenesis to ferry in much-needed oxygen and nutrients that encourage the growth of tumours. There is now irrefutable data demonstrating that the immune contexture of breast tumours can influence growth and metastasis. A higher immune cell count in invasive breast cancer predicts prognosis and response to chemotherapy. We are beginning now to define the specific innate and adaptive immune cells present in breast cancer and their role not just in the progression of invasive disease, but also in the development of pre-invasive lesions and their transition to malignant tumours. This review article focusses on the immune cells present in early stage breast cancer and their relationship with the immunoediting process involved in tumour advancement. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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19 pages, 3850 KiB  
Review
Cell Heterogeneity and Phenotypic Plasticity in Metastasis Formation: The Case of Colon Cancer
by Miriam Teeuwssen and Riccardo Fodde
Cancers 2019, 11(9), 1368; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091368 - 14 Sep 2019
Cited by 41 | Viewed by 6069 | Correction
Abstract
The adenoma-to-carcinoma progression in colon cancer is driven by a sequential accumulation of genetic alterations at specific tumor suppressors and oncogenes. In contrast, the multistage route from the primary site to metastasis formation is underlined by phenotypic plasticity, i.e., the capacity of disseminated [...] Read more.
The adenoma-to-carcinoma progression in colon cancer is driven by a sequential accumulation of genetic alterations at specific tumor suppressors and oncogenes. In contrast, the multistage route from the primary site to metastasis formation is underlined by phenotypic plasticity, i.e., the capacity of disseminated tumor cells to undergo transiently and reversible transformations in order to adapt to the ever-changing environmental contexts. Notwithstanding the considerable body of evidence in support of the role played by epithelial-to-mesenchymal transition (EMT)/mesenchymal-to-epithelial transition (MET) in metastasis, its rate-limiting function, the detailed underlying cellular and molecular mechanisms, and the extension of the necessary morphologic and epigenetic changes are still a matter of debate. Rather than leading to a complete epithelial or mesenchymal state, the EMT/MET-program generates migrating cancer cells displaying intermediate phenotypes featuring both epithelial and mesenchymal characteristics. In this review, we will address the role of colon cancer heterogeneity and phenotypic plasticity in metastasis formation and the contribution of EMT to these processes. The alleged role of hybrid epithelial/mesenchymal (E/M) in collective and/or single-cell migration during local dissemination at the primary site and more systemic spreading will also be highlighted. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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17 pages, 3060 KiB  
Review
Exploring Tumor Heterogeneity Using PET Imaging: The Big Picture
by Clément Bailly, Caroline Bodet-Milin, Mickaël Bourgeois, Sébastien Gouard, Catherine Ansquer, Matthieu Barbaud, Jean-Charles Sébille, Michel Chérel, Françoise Kraeber-Bodéré and Thomas Carlier
Cancers 2019, 11(9), 1282; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091282 - 31 Aug 2019
Cited by 40 | Viewed by 5228
Abstract
Personalized medicine represents a major goal in oncology. It has its underpinning in the identification of biomarkers with diagnostic, prognostic, or predictive values. Nowadays, the concept of biomarker no longer necessarily corresponds to biological characteristics measured ex vivo but includes complex physiological characteristics [...] Read more.
Personalized medicine represents a major goal in oncology. It has its underpinning in the identification of biomarkers with diagnostic, prognostic, or predictive values. Nowadays, the concept of biomarker no longer necessarily corresponds to biological characteristics measured ex vivo but includes complex physiological characteristics acquired by different technologies. Positron-emission-tomography (PET) imaging is an integral part of this approach by enabling the fine characterization of tumor heterogeneity in vivo in a non-invasive way. It can effectively be assessed by exploring the heterogeneous distribution and uptake of a tracer such as 18F-fluoro-deoxyglucose (FDG) or by using multiple radiopharmaceuticals, each providing different information. These two approaches represent two avenues of development for the research of new biomarkers in oncology. In this article, we review the existing evidence that the measurement of tumor heterogeneity with PET imaging provide essential information in clinical practice for treatment decision-making strategy, to better select patients with poor prognosis for more intensive therapy or those eligible for targeted therapy. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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24 pages, 1206 KiB  
Review
Impact of Tumor and Immunological Heterogeneity on the Anti-Cancer Immune Response
by Carolyn Shembrey, Nicholas D. Huntington and Frédéric Hollande
Cancers 2019, 11(9), 1217; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091217 - 21 Aug 2019
Cited by 31 | Viewed by 7131
Abstract
Metastatic tumors are the primary cause of cancer-related mortality. In recent years, interest in the immunologic control of malignancy has helped establish escape from immunosurveillance as a critical requirement for incipient metastases. Our improved understanding of the immune system’s interactions with cancer cells [...] Read more.
Metastatic tumors are the primary cause of cancer-related mortality. In recent years, interest in the immunologic control of malignancy has helped establish escape from immunosurveillance as a critical requirement for incipient metastases. Our improved understanding of the immune system’s interactions with cancer cells has led to major therapeutic advances but has also unraveled a previously unsuspected level of complexity. This review will discuss the vast spatial and functional heterogeneity in the tumor-infiltrating immune system, with particular focus on natural killer (NK) cells, as well as the impact of tumor cell-specific factors, such as secretome composition, receptor–ligand repertoire, and neoantigen diversity, which can further drive immunological heterogeneity. We emphasize how tumor and immunological heterogeneity may undermine the efficacy of T-cell directed immunotherapies and explore the potential of NK cells to be harnessed to circumvent these limitations. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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14 pages, 690 KiB  
Review
Biological Significance of Tumor Heterogeneity in Esophageal Squamous Cell Carcinoma
by Lehang Lin and De-Chen Lin
Cancers 2019, 11(8), 1156; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081156 - 12 Aug 2019
Cited by 39 | Viewed by 11077
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy, with hitherto dismal clinical outcome. Genomic analyses of patient samples reveal a complex heterogeneous landscape for ESCC, which presents in both intertumor and intratumor forms, manifests at both genomic and epigenomic levels, [...] Read more.
Esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy, with hitherto dismal clinical outcome. Genomic analyses of patient samples reveal a complex heterogeneous landscape for ESCC, which presents in both intertumor and intratumor forms, manifests at both genomic and epigenomic levels, and contributes significantly to tumor evolution, drug resistance, and metastasis. Here, we review the important molecular characteristics underlying ESCC heterogeneity, with an emphasis on genomic aberrations and their functional contribution to cancer evolutionary trajectories. We further discuss how novel experimental tools, including single-cell sequencing and three-dimensional organoids, may advance our understanding of tumor heterogeneity. Lastly, we suggest that deciphering the mechanisms governing tumor heterogeneity holds the potential to developing precision therapeutics for ESCC patients. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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17 pages, 2239 KiB  
Review
Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance
by David E. Korenchan and Robert R. Flavell
Cancers 2019, 11(7), 1026; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071026 - 20 Jul 2019
Cited by 40 | Viewed by 7208
Abstract
Dysregulation of pH in solid tumors is a hallmark of cancer. In recent years, the role of altered pH heterogeneity in space, between benign and aggressive tissues, between individual cancer cells, and between subcellular compartments, has been steadily elucidated. Changes in temporal pH-related [...] Read more.
Dysregulation of pH in solid tumors is a hallmark of cancer. In recent years, the role of altered pH heterogeneity in space, between benign and aggressive tissues, between individual cancer cells, and between subcellular compartments, has been steadily elucidated. Changes in temporal pH-related processes on both fast and slow time scales, including altered kinetics of bicarbonate-CO2 exchange and its effects on pH buffering and gradual, progressive changes driven by changes in metabolism, are further implicated in phenotypic changes observed in cancers. These discoveries have been driven by advances in imaging technologies. This review provides an overview of intra- and extracellular pH alterations in time and space reflected in cancer cells, as well as the available technology to study pH spatiotemporal heterogeneity. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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21 pages, 6769 KiB  
Review
Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma
by Susanna Leskela, Belen Pérez-Mies, Juan Manuel Rosa-Rosa, Eva Cristobal, Michele Biscuola, María L. Palacios-Berraquero, SuFey Ong, Xavier Matias-Guiu Guia and José Palacios
Cancers 2019, 11(7), 964; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11070964 - 09 Jul 2019
Cited by 52 | Viewed by 6102
Abstract
Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) [...] Read more.
Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC. However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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10 pages, 4113 KiB  
Review
The Impact of Tumor Eco-Evolution in Renal Cell Carcinoma Sampling
by Estíbaliz López-Fernández and José I. López
Cancers 2018, 10(12), 485; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10120485 - 04 Dec 2018
Cited by 10 | Viewed by 3326
Abstract
Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to [...] Read more.
Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist’s daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
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