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Cancers
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Cancer Evolution
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Cancer Evolution

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 20236

Special Issue Editor

Prof. Dr. Henry H. Heng

E-Mail Website
Guest Editor
Center for Molecular Medicine and Genomics, and Pathology Department, Wayne State University School of Medicine, Detroit, MI 48201, USA
Interests: cancer evolution; chromosomal coding; karyotype mediated-drug resistance; fuzzy inheritance; genome instability and chaos; genome theory; mechanism of heterogeneity; system inheritance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The current Cancer Genome Project has revealed a big surprise: in most cancer types, while it is difficult to identify long-expected common cancer gene mutations, multiple levels of genetic and nongenetic heterogeneity are observed overwhelmingly.  Such large-scale sequencing data, especially single-cell sequencing data, has challenged the gene mutation theory of cancer, which predicted that sequencing large numbers of clinical samples should reveal a limited number of common cancer gene mutations.  Identification of these common mutations is the main rationale and promise for the Cancer Genome Project, as these targetable “bad genes” are the key both for diagnosis and effective therapy.

Darwinian evolutionary concepts have been used to reconcile these puzzling outcomes. Accordingly, many terminologies have been frequently used in cancer literature, such as driver mutations, passenger mutations, neutral or positive selection, clonal expansion or sub-clonal heterogeneity, linear or branch evolution, stepwise or punctuated evolution, and gene mutations or CNVs or genome chaos.

Although it is helpful to use evolutionary principles to explain the massive diversity of genomic data, the clinical prediction value of sequencing data is limited, especially when the gene mutation landscape is highly dynamic and can drastically change immediately following targeting therapy. Clearly, both technical platforms and computational tools as well as, perhaps more importantly, new evolutionary frameworks, are needed to explain such complexity and confusion.

The aim of this Special Issue is to highlight the recent advances of cancer evolutionary studies, both from conceptual and methodological perspectives. By integrating sequencing information with evolutionary mechanisms, this Special Issue will also discuss the future direction of evolutionary cancer research.

This issue covers the following topics:

  • General evolutionary pattern of specific types of cancer
  • Evolutionary model for cancer initiation, progress, metastasis, and drug resistance
  • Evolutionary model of heterogeneity
  • New technical platforms/bioinformatic tools to study cancer evolution
  • The relationship between gene mutation mediated micro- and genome re-organization mediated macrocellular evolution
  • The interaction among epigenetic regulation, gene mutations, copy number variations, and genome chaos in cancer evolution
  • Can Darwinian concepts explain cancer evolution?

Prof. Henry H. Heng
Guest Editor

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

  • Clonal expansion
  • Genomic landscape
  • Genome chaos
  • Heterogeneity
  • Macro- and micro-cellular evolution
  • Punctuated cancer evolution

Published Papers (7 papers)

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Research

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8 pages, 566 KiB  
Communication
A Proposed Trial Design for the Treatment of Widely Metastatic Ewing Sarcoma Inspired by Evolutionary Dynamics
by Jonathan Metts, Thomas Russell, Damon Reed and Matteo Trucco
Cancers 2022, 14(3), 736; https://doi.org/10.3390/cancers14030736 - 31 Jan 2022
Cited by 2 | Viewed by 2203
Abstract
Metastatic Ewing sarcoma has dismal long-term survival despite multiple attempts to intensify standard therapy through the addition of new agents to the existing chemotherapy backbone. Here, based on the application of evolutionary dynamics to pediatric sarcoma, we propose an alternative treatment strategy that [...] Read more.
Metastatic Ewing sarcoma has dismal long-term survival despite multiple attempts to intensify standard therapy through the addition of new agents to the existing chemotherapy backbone. Here, based on the application of evolutionary dynamics to pediatric sarcoma, we propose an alternative treatment strategy that varies exposure to agents and dosing intensities, termed sequential second-strike therapy (SSST). We announce an upcoming clinical trial to apply these principles to patients with widely metastatic Ewing sarcoma, those with metastatic disease beyond the lungs. Full article
(This article belongs to the Special Issue Cancer Evolution)
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13 pages, 2278 KiB  
Article
Non-Invasive Ultrasonic Description of Tumor Evolution
by Jerome Griffon, Delphine Buffello, Alain Giron, S. Lori Bridal and Michele Lamuraglia
Cancers 2021, 13(18), 4560; https://doi.org/10.3390/cancers13184560 - 11 Sep 2021
Cited by 1 | Viewed by 1496
Abstract
Purpose: There is a clinical need to better non-invasively characterize the tumor microenvironment in order to reveal evidence of early tumor response to therapy and to better understand therapeutic response. The goals of this work are first to compare the sensitivity to modifications [...] Read more.
Purpose: There is a clinical need to better non-invasively characterize the tumor microenvironment in order to reveal evidence of early tumor response to therapy and to better understand therapeutic response. The goals of this work are first to compare the sensitivity to modifications occurring during tumor growth for measurements of tumor volume, immunohistochemistry parameters, and emerging ultrasound parameters (Shear Wave Elastography (SWE) and dynamic Contrast-Enhanced Ultrasound (CEUS)), and secondly, to study the link between the different parameters. Methods: Five different groups of 9 to 10 BALB/c female mice with subcutaneous CT26 tumors were imaged using B-mode morphological imaging, SWE, and CEUS at different dates. Whole-slice immunohistological data stained for the nuclei, T lymphocytes, apoptosis, and vascular endothelium from these tumors were analyzed. Results: Tumor volume and three CEUS parameters (Time to Peak, Wash-In Rate, and Wash-Out Rate) significantly changed over time. The immunohistological parameters, CEUS parameters, and SWE parameters showed intracorrelation. Four immunohistological parameters (the number of T lymphocytes per mm2 and its standard deviation, the percentage area of apoptosis, and the colocalization of apoptosis and vascular endothelium) were correlated with the CEUS parameters (Time to Peak, Wash-In Rate, Wash-Out Rate, and Mean Transit Time). The SWE parameters were not correlated with the CEUS parameters nor with the immunohistological parameters. Conclusions: US imaging can provide additional information on tumoral changes. This could help to better explore the effect of therapies on tumor evolution, by studying the evolution of the parameters over time and by studying their correlations. Full article
(This article belongs to the Special Issue Cancer Evolution)
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Review

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13 pages, 1691 KiB  
Review
Emerging Role of Chimeric RNAs in Cell Plasticity and Adaptive Evolution of Cancer Cells
by Sumit Mukherjee, Henry H. Heng and Milana Frenkel-Morgenstern
Cancers 2021, 13(17), 4328; https://doi.org/10.3390/cancers13174328 - 27 Aug 2021
Cited by 10 | Viewed by 2892
Abstract
Gene fusions can give rise to somatic alterations in cancers. Fusion genes have the potential to create chimeric RNAs, which can generate the phenotypic diversity of cancer cells, and could be associated with novel molecular functions related to cancer cell survival and proliferation. [...] Read more.
Gene fusions can give rise to somatic alterations in cancers. Fusion genes have the potential to create chimeric RNAs, which can generate the phenotypic diversity of cancer cells, and could be associated with novel molecular functions related to cancer cell survival and proliferation. The expression of chimeric RNAs in cancer cells might impact diverse cancer-related functions, including loss of apoptosis and cancer cell plasticity, and promote oncogenesis. Due to their recurrence in cancers and functional association with oncogenic processes, chimeric RNAs are considered biomarkers for cancer diagnosis. Several recent studies demonstrated that chimeric RNAs could lead to the generation of new functionality for the resistance of cancer cells against drug therapy. Therefore, targeting chimeric RNAs in drug resistance cancer could be useful for developing precision medicine. So, understanding the functional impact of chimeric RNAs in cancer cells from an evolutionary perspective will be helpful to elucidate cancer evolution, which could provide a new insight to design more effective therapies for cancer patients in a personalized manner. Full article
(This article belongs to the Special Issue Cancer Evolution)
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12 pages, 1027 KiB  
Review
Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution
by Giusi Russo, Alfonso Tramontano, Ilaria Iodice, Lorenzo Chiariotti and Antonio Pezone
Cancers 2021, 13(8), 1800; https://doi.org/10.3390/cancers13081800 - 09 Apr 2021
Cited by 14 | Viewed by 3069
Abstract
Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which [...] Read more.
Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which means that the changes of epigenetic traits are randomly generated, but strongly selected by deterministic events. Disordered changes of DNA methylation profiles are the hallmarks of all cancer types, but it is not clear if aberrant methylation is the cause or the consequence of cancer evolution. Critical points to address are the profound epigenetic intra- and inter-tumor heterogeneity and the nature of the heterogeneity of the methylation patterns in each single cell in the tumor population. To analyze the methylation heterogeneity of tumors, new technological and informatic tools have been developed. This review discusses the state of the art of DNA methylation analysis and new approaches to reduce or solve the complexity of methylated alleles in DNA or cell populations. Full article
(This article belongs to the Special Issue Cancer Evolution)
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18 pages, 388 KiB  
Review
How Chaotic Is Genome Chaos?
by James A. Shapiro
Cancers 2021, 13(6), 1358; https://doi.org/10.3390/cancers13061358 - 17 Mar 2021
Cited by 8 | Viewed by 2757
Abstract
Cancer genomes evolve in a punctuated manner during tumor evolution. Abrupt genome restructuring at key steps in this evolution has been called “genome chaos.” To answer whether widespread genome change is truly chaotic, this review (i) summarizes the limited number of cell and [...] Read more.
Cancer genomes evolve in a punctuated manner during tumor evolution. Abrupt genome restructuring at key steps in this evolution has been called “genome chaos.” To answer whether widespread genome change is truly chaotic, this review (i) summarizes the limited number of cell and molecular systems that execute genome restructuring, (ii) describes the characteristic signatures of DNA changes that result from activity of those systems, and (iii) examines two cases where genome restructuring is determined to a significant degree by cell type or viral infection. The conclusion is that many restructured cancer genomes display sufficiently unchaotic signatures to identify the cellular systems responsible for major oncogenic transitions, thereby identifying possible targets for therapies to inhibit tumor progression to greater aggressiveness. Full article
(This article belongs to the Special Issue Cancer Evolution)
20 pages, 429 KiB  
Review
Tumour Evolution and Seed and Soil Mechanism in Pancreatic Metastases of Renal Cell Carcinoma
by Franz Sellner, Sabine Thalhammer and Martin Klimpfinger
Cancers 2021, 13(6), 1342; https://doi.org/10.3390/cancers13061342 - 16 Mar 2021
Cited by 9 | Viewed by 1728
Abstract
In metastatic renal cell carcinoma, pancreatic metastases can appear in two clinical manifestations: (a) very rarely as isolated pancreatic metastases and (b) in the context with multi-organ metastatic disease. Both courses are characterised by rare, unusual clinical features. For isolated pancreatic metastases, the [...] Read more.
In metastatic renal cell carcinoma, pancreatic metastases can appear in two clinical manifestations: (a) very rarely as isolated pancreatic metastases and (b) in the context with multi-organ metastatic disease. Both courses are characterised by rare, unusual clinical features. For isolated pancreatic metastases, the literature shows no effect on survival in all 11 publications that examined the effect of singular versus multiple pancreatic metastases; a lack of effect on survival time was also present in all 8 studies on pancreatic metastases size, in 7 of 8 studies on the influence of disease-free interval (DFI), and in 6 of 7 studies on the influence of synchronous versus metachronous metastases. In multi-organ site metastases observations, on the other hand, all five available references showed significantly better results in patients with concurrent pancreatic metastases compared to those without pancreatic metastases, although the total number of affected organs in the pancreatic metastases cohort was larger. Tumour volume-dependent risk factors thus remain surprisingly ineffective in both groups, which contradicts the usual behaviour of solid tumours. The reasons for this unusual behaviour and possible relations to tumour evolution and the hypothesis of an influence of a seed and soil mechanism in the occurrence of pancreatic metastases in metastatic renal cell carcinoma are discussed. Full article
(This article belongs to the Special Issue Cancer Evolution)
16 pages, 1169 KiB  
Review
Reviving the Autopsy for Modern Cancer Evolution Research
by Tamsin Joy Robb, Rexson Tse and Cherie Blenkiron
Cancers 2021, 13(3), 409; https://doi.org/10.3390/cancers13030409 - 22 Jan 2021
Cited by 6 | Viewed by 4515
Abstract
Outstanding questions plaguing oncologists, centred around tumour evolution and heterogeneity, include the development of treatment resistance, immune evasion, and optimal drug targeting strategies. Such questions are difficult to study in limited cancer tissues collected during a patient’s routine clinical care, and may be [...] Read more.
Outstanding questions plaguing oncologists, centred around tumour evolution and heterogeneity, include the development of treatment resistance, immune evasion, and optimal drug targeting strategies. Such questions are difficult to study in limited cancer tissues collected during a patient’s routine clinical care, and may be better investigated in the breadth of cancer tissues that may be permissible to collect during autopsies. We are starting to better understand key tumour evolution challenges based on advances facilitated by autopsy studies completed to date. This review article explores the great progress in understanding that cancer tissues collected at autopsy have already enabled, including the shared origin of metastatic cells, the importance of early whole-genome doubling events for amplifying genes needed for tumour survival, and the creation of a wealth of tissue resources powered to answer future questions, including patient-derived xenografts, cell lines, and a wide range of banked tissues. We also highlight the future role of these programmes in advancing our understanding of cancer evolution. The research autopsy provides a special opportunity for cancer patients to give the ultimate gift—to selflessly donate their tissues towards better cancer care. Full article
(This article belongs to the Special Issue Cancer Evolution)
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