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Cancers
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Tumor Evolution: Progression, Metastasis and Therapeutic Response
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Tumor Evolution: Progression, Metastasis and Therapeutic Response

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

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 76390

Special Issue Editor

Dr. Theodoros Rampias

E-Mail Website
Guest Editor
Biomedical Research Foundation of the Academy of Athens (BRFAA), 11741 Athens, Greece
Interests: genome integrity; epigenetic regulation; gene expression; translation; viruses; molecular virology; viruses’ evolution
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in cancer genomics have revealed that solid tumors often consist of multiple genetically and spatially distinct subpopulations. In addition, cancer cells within different subpopulations can evolve, acquiring genetic and epigenetic alterations over time that affect their interactions with the tissue microenvironment and the immune system.

During tumor progression, these evolutionary dynamics have the potential to generate subclones that are resistant to drug therapy or have metastatic potential. Understanding the molecular mechanisms driving cancer heterogeneity, evolution, chemoresistance, invasion, migration and distant colonization is helping us to identify promising biomarkers for therapeutic targeting.

For this Special Issue of Cancers, we invite authors to submit contributions that provide novel findings in the field of cancer progression and evolution. In particular (but not limited to), insights in the areas of tumor heterogeneity, mutation acquisition, DNA repair, epigenetic deregulation, transcriptional plasticity, chemoresistance and therapeutic response, immune escape, tumor microenvironment, recurrence and metastasis with respect to tumor evolution are of great interest. Reviews that highlight new findings in the above areas are also welcome.

Prof. Dr. Theodoros Rampias
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

  • tumor heterogeneity
  • clonal evolution
  • mutations
  • metastasis
  • plasticity
  • epigenetics
  • DNA repair
  • chemoresistance
  • genomic instability
  • tumor microenvironment
  • adaptive immune resistance

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Published Papers (20 papers)

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Editorial

Jump to: Research, Review

4 pages, 535 KiB  
Editorial
Cancer Evolution in Precision Medicine Era
by Dimitris Karagiannis and Theodoros Rampias
Cancers 2022, 14(8), 1885; https://doi.org/10.3390/cancers14081885 - 08 Apr 2022
Cited by 2 | Viewed by 2023
Abstract
Recent advances in our understanding of cancer, driven mainly by the emergence of new technologies have highlighted that heterogeneity shapes not only the genetic profile of tumors but also their epigenetic and gene expression profile [...] Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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8 pages, 1235 KiB  
Editorial
Exploring the Eco-Evolutionary Dynamics of Tumor Subclones
by Theodoros Rampias
Cancers 2020, 12(11), 3436; https://doi.org/10.3390/cancers12113436 - 19 Nov 2020
Cited by 1 | Viewed by 1799
Abstract
Mutational processes constantly shape the cancer genome and defects in DNA repair pathways of tumor cells facilitate the accumulation of genomic alterations [...] Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Research

Jump to: Editorial, Review

15 pages, 4493 KiB  
Article
Interactions Networks for Primary Heart Sarcomas
by Styliani A. Geronikolou, Athanasia Pavlopoulou, George P. Chrousos and Dennis V. Cokkinos
Cancers 2021, 13(15), 3882; https://doi.org/10.3390/cancers13153882 - 01 Aug 2021
Cited by 1 | Viewed by 2402
Abstract
Personalized medicine incorporates genetic information into medical practice so as to optimize the management of chronic diseases. In rare diseases, such as heart cancer (incidence 0.0017–0.33%), this may be elusive. Ninety-five percent of the cases are due to secondary involvementwith the neoplasm originating [...] Read more.
Personalized medicine incorporates genetic information into medical practice so as to optimize the management of chronic diseases. In rare diseases, such as heart cancer (incidence 0.0017–0.33%), this may be elusive. Ninety-five percent of the cases are due to secondary involvementwith the neoplasm originating in the lungs, breasts, kidney, blood, or skin. The clinical manifestations of heart tumors (benign or malignant) include heart failure, hypertension, and cardiac arrhythmias of varying severity, frequently resulting in blood vessel emboli, including strokes. This study aims to explain the pathophysiology and contribute to a P4 medicine model for use by cardiologists, pathologists, and oncologists. We created six gene/protein heart-related and tumor-related targets high-confidence interactomes, which unfold the main pathways that may lead to cardiac diseases (heart failure, hypertension, coronary artery disease, arrhythmias), i.e., the sympathetic nervous system, the renin-angiotensin-aldosterone axis and the endothelin pathway, and excludes others, such as the K oxidase or cytochrome P450 pathways. We concluded that heart cancer patients could be affected by beta-adrenergic blockers, ACE inhibitors, QT-prolonging antiarrhythmic drugs, antibiotics, and antipsychotics. Interactomes may elucidate unknown pathways, adding to patient/survivor wellness during/after chemo- and/or radio-therapy. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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15 pages, 4232 KiB  
Article
Evaluation of Collagen Alterations in Early Precursor Lesions of High Grade Serous Ovarian Cancer by Second Harmonic Generation Microscopy and Mass Spectrometry
by Kristal L. Gant, Alexander N. Jambor, Zihui Li, Eric C. Rentchler, Paul Weisman, Lingjun Li, Manish S. Patankar and Paul J. Campagnola
Cancers 2021, 13(11), 2794; https://doi.org/10.3390/cancers13112794 - 04 Jun 2021
Cited by 14 | Viewed by 3256
Abstract
Background: The collagen architecture in high grade serous ovarian cancer (HGSOC) is highly remodeled compared to the normal ovary and the fallopian tubes (FT). We previously used Second Harmonic Generation (SHG) microscopy and machine learning to classify the changes in collagen fiber morphology [...] Read more.
Background: The collagen architecture in high grade serous ovarian cancer (HGSOC) is highly remodeled compared to the normal ovary and the fallopian tubes (FT). We previously used Second Harmonic Generation (SHG) microscopy and machine learning to classify the changes in collagen fiber morphology occurring in serous tubal intraepithelial carcinoma (STIC) lesions that are concurrent with HGSOC. We now extend these studies to examine collagen remodeling in pure p53 signatures, STICs and normal regions in tissues that have no concurrent HGSOC. This is an important distinction as high-grade disease can result in distant collagen changes through a field effect mechanism. Methods: We trained a linear discriminant model based on SHG texture and image features as a classifier to discriminate the tissue groups. We additionally performed mass spectrometry analysis of normal and HGSOC tissues to associate the differential expression of collagen isoforms with collagen fiber morphology alterations. Results: We quantified the differences in the collagen architecture between normal tissue and the precursors with good classification accuracy. Through proteomic analysis, we identified the downregulation of single α-chains including those for Col I and III, where these results are consistent with our previous SHG-based supramolecular analyses. Conclusion: This work provides new insights into ECM remodeling in early ovarian cancer and suggests the combined use of SHG microscopy and mass spectrometry as a new diagnostic/prognostic approach. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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13 pages, 832 KiB  
Article
Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity
by Zoi Kanaki, Alexandra Voutsina, Athina Markou, Ioannis S. Pateras, Konstantinos Potaris, Margaritis Avgeris, Periklis Makrythanasis, Emmanouil I. Athanasiadis, Ioannis Vamvakaris, Eleni Patsea, Konstantinos Vachlas, Evi Lianidou, Vassilis Georgoulias, Athanasios Kotsakis and Apostolos Klinakis
Cancers 2021, 13(10), 2446; https://doi.org/10.3390/cancers13102446 - 18 May 2021
Cited by 4 | Viewed by 2307
Abstract
Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and [...] Read more.
Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients’ peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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14 pages, 2365 KiB  
Article
Prognostic Significance of Gene Expression and DNA Methylation Markers in Circulating Tumor Cells and Paired Plasma Derived Exosomes in Metastatic Castration Resistant Prostate Cancer
by Martha Zavridou, Areti Strati, Evangelos Bournakis, Stavroula Smilkou, Victoria Tserpeli and Evi Lianidou
Cancers 2021, 13(4), 780; https://doi.org/10.3390/cancers13040780 - 13 Feb 2021
Cited by 40 | Viewed by 4219
Abstract
Liquid biopsy, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers [...] Read more.
Liquid biopsy, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers in CTCs and paired plasma-derived exosomes and evaluated their prognostic significance in metastatic castration resistant prostate cancer. This prospective liquid biopsy (LB) study was based on a group of 62 metastatic castration resistant prostate cancer (mCRPC) patients and 10 healthy donors (HD) as controls. Identical blood draws were used to: (a) enumerate CTC and tumor-derived extracellular vesicles (tdEVs) using CellSearch (CS) and (b) analyze CTCs and paired plasma-derived exosomes at the gene expression and DNA methylation level. CTCs were enumerated using CellSearch in 57/62 patients, with values ranging from 5 to 854 cells/7.5 mL PB. Our results revealed for the first time a significantly higher positivity of gene expression markers (CK-8, CK-18, TWIST1, PSMA, AR-FL, AR-V7, AR-567 and PD-L1 mRNA) in EpCAM-positive CTCs compared to plasma-derived exosomes. GSTP1, RASSF1A and SCHLAFEN were methylated both in CTC and exosomes. In CTCs, Kaplan–Meier analysis revealed that CK-19 (p = 0.009), PSMA (p = 0.001), TWIST1 (p = 0.001) expression and GSTP1 (p = 0.001) methylation were correlated with OS, while in exosomes GSTP1 (p = 0.007) and RASSF1A (p = 0.001) methylation was correlated with OS. Our direct comparison study of CTCs and exosomes at gene expression and DNA methylation level, revealed for the first time a significantly higher positivity in EpCAM-positive CTCs compared to plasma-derived exosomes. Future perspective of this study should be the evaluation of clinical utility of molecular biomarkers in CTCs and exosomes on independent multicentric cohorts with mCRPC patients. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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19 pages, 4352 KiB  
Article
Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican
by David Brunn, Kati Turkowski, Stefan Günther, Andreas Weigert, Thomas Muley, Mark Kriegsmann, Hauke Winter, Reinhard H. Dammann, Georgios T. Stathopoulos, Michael Thomas, Andreas Guenther, Friedrich Grimminger, Soni S. Pullamsetti, Werner Seeger and Rajkumar Savai
Cancers 2021, 13(2), 208; https://doi.org/10.3390/cancers13020208 - 08 Jan 2021
Cited by 10 | Viewed by 4870
Abstract
Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently [...] Read more.
Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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21 pages, 3516 KiB  
Article
tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome
by Maria-Alexandra Papadimitriou, Margaritis Avgeris, Panagiotis Levis, Evangelia Ch. Papasotiriou, Georgios Kotronopoulos, Konstantinos Stravodimos and Andreas Scorilas
Cancers 2020, 12(12), 3661; https://doi.org/10.3390/cancers12123661 - 06 Dec 2020
Cited by 31 | Viewed by 3701
Abstract
The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of [...] Read more.
The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of the TCGA-BLCA project highlighted 5′-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5′-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient’s death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5′-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5′-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; p = 0.033) and poor survival (multivariate Cox: HR = 2.151; p = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5′-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients’ progression. In conclusion, increased 5′-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients’ prognostication. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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21 pages, 6730 KiB  
Article
Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain
by Young Min Lee, Seok Hyun Kim, Minseok S. Kim, Dae Cheol Kim, Eun Hee Lee, Ju Suk Lee, Sung-Hun Lee and Young Zoon Kim
Cancers 2020, 12(12), 3632; https://doi.org/10.3390/cancers12123632 - 04 Dec 2020
Cited by 13 | Viewed by 2006
Abstract
Purpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired samples of lung adenocarcinoma and [...] Read more.
Purpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. Results: The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 linear = −2.723) decreased in reverse proportion. Conclusions: The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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26 pages, 7367 KiB  
Article
Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia
by Miriam G. Contreras Mostazo, Nina Kurrle, Marta Casado, Dominik Fuhrmann, Islam Alshamleh, Björn Häupl, Paloma Martín-Sanz, Bernhard Brüne, Hubert Serve, Harald Schwalbe, Frank Schnütgen, Silvia Marin and Marta Cascante
Cancers 2020, 12(11), 3443; https://doi.org/10.3390/cancers12113443 - 19 Nov 2020
Cited by 7 | Viewed by 3692
Abstract
Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, [...] Read more.
Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Graphical abstract

21 pages, 4277 KiB  
Article
Single-Cell RNA Sequencing Unravels Heterogeneity of the Stromal Niche in Cutaneous Melanoma Heterogeneous Spheroids
by Jiří Novotný, Karolína Strnadová, Barbora Dvořánková, Šárka Kocourková, Radek Jakša, Pavel Dundr, Václav Pačes, Karel Smetana, Jr., Michal Kolář and Lukáš Lacina
Cancers 2020, 12(11), 3324; https://doi.org/10.3390/cancers12113324 - 10 Nov 2020
Cited by 17 | Viewed by 4805
Abstract
Heterogeneous spheroids have recently acquired a prominent position in melanoma research because they incorporate microenvironmental cues relevant for melanoma. In this study, we focused on the analysis of microenvironmental factors introduced in melanoma heterogeneous spheroids by different dermal fibroblasts. We aimed to map [...] Read more.
Heterogeneous spheroids have recently acquired a prominent position in melanoma research because they incorporate microenvironmental cues relevant for melanoma. In this study, we focused on the analysis of microenvironmental factors introduced in melanoma heterogeneous spheroids by different dermal fibroblasts. We aimed to map the fibroblast diversity resulting from previously acquired damage caused by exposure to extrinsic and intrinsic stimuli. To construct heterogeneous melanoma spheroids, we used normal dermal fibroblasts from the sun-protected skin of a juvenile donor. We compared them to the fibroblasts from the sun-exposed photodamaged skin of an adult donor. Further, we analysed the spheroids by single-cell RNA sequencing. To validate transcriptional data, we also compared the immunohistochemical analysis of heterogeneous spheroids to melanoma biopsies. We have distinguished three functional clusters in primary human fibroblasts from melanoma spheroids. These clusters differed in the expression of (a) extracellular matrix-related genes, (b) pro-inflammatory factors, and (c) TGFβ signalling superfamily. We observed a broader deregulation of gene transcription in previously photodamaged cells. We have confirmed that pro-inflammatory cytokine IL-6 significantly enhances melanoma invasion to the extracellular matrix in our model. This supports the opinion that the aspects of ageing are essential for reliable melanoma 3D modelling in vitro. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Graphical abstract

21 pages, 2090 KiB  
Article
Clonal Evolution and Timing of Metastatic Colorectal Cancer
by Sarah Siraj, Tariq Masoodi, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Saeeda O. Ahmed, Wafaa N. AlBalawy, Khadija A. Al-Obaisi, Sandeep K. Parvathareddy, Hadeel M. AlManea, Hussah F. AlHussaini, Alaa Abduljabbar, Samar Alhomoud, Fouad H. Al-Dayel, Fowzan S. Alkuraya and Khawla S. Al-Kuraya
Cancers 2020, 12(10), 2938; https://doi.org/10.3390/cancers12102938 - 12 Oct 2020
Cited by 8 | Viewed by 2984
Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. [...] Read more.
Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours (n = 92 tumour regions) and metastases (n = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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17 pages, 3781 KiB  
Article
The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer
by Tatiana S. Gerashchenko, Sofia Y. Zolotaryova, Artem M. Kiselev, Liubov A. Tashireva, Nikita M. Novikov, Nadezhda V. Krakhmal, Nadezhda V. Cherdyntseva, Marina V. Zavyalova, Vladimir M. Perelmuter and Evgeny V. Denisov
Cancers 2020, 12(7), 1909; https://doi.org/10.3390/cancers12071909 - 15 Jul 2020
Cited by 10 | Viewed by 3035
Abstract
Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used [...] Read more.
Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Review

Jump to: Editorial, Research

29 pages, 3124 KiB  
Review
HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity
by Dimitris Karagiannis and Theodoros Rampias
Cancers 2021, 13(14), 3575; https://doi.org/10.3390/cancers13143575 - 16 Jul 2021
Cited by 33 | Viewed by 3905
Abstract
Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes [...] Read more.
Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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41 pages, 6004 KiB  
Review
Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution
by Yelyzaveta Shlyakhtina, Katherine L. Moran and Maximiliano M. Portal
Cancers 2021, 13(6), 1380; https://doi.org/10.3390/cancers13061380 - 18 Mar 2021
Cited by 32 | Viewed by 6674
Abstract
Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized [...] Read more.
Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized and rather cryptic. Nevertheless, although our current knowledge is fragmentary, data collected to date suggest that most tumours display features compatible with a diverse array of evolutionary paths, suggesting that most of the existing macro-evolutionary models find their avatar in cancer biology. Herein, we discuss an up-to-date view of the fundamental genetic and non-genetic mechanisms underlying tumour evolution with the aim of concurring into an integrated view of the evolutionary forces at play throughout the emergence and progression of the disease and into the acquisition of resistance to diverse therapeutic paradigms. Our ultimate goal is to delve into the intricacies of genetic and non-genetic networks underlying tumour evolution to build a framework where both core concepts are considered non-negligible and equally fundamental. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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33 pages, 397 KiB  
Review
Anti-Cancer Auto-Antibodies: Roles, Applications and Open Issues
by Hugo de Jonge, Luisa Iamele, Maristella Maggi, Greta Pessino and Claudia Scotti
Cancers 2021, 13(4), 813; https://doi.org/10.3390/cancers13040813 - 15 Feb 2021
Cited by 24 | Viewed by 4559
Abstract
Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels. However, recent evidence is accumulating on the presence of auto-antibodies against single or selected panels of auto-antigens in many types of cancer. Auto-antibodies might initially represent an [...] Read more.
Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels. However, recent evidence is accumulating on the presence of auto-antibodies against single or selected panels of auto-antigens in many types of cancer. Auto-antibodies might initially represent an epiphenomenon derived from the inflammatory environment induced by the tumor. However, their effect on tumor evolution can be crucial, as is discussed in this paper. It has been demonstrated that some of these auto-antibodies can be used for early detection and cancer staging, as well as for monitoring of cancer regression during treatment and follow up. Interestingly, certain auto-antibodies were found to promote cancer progression and metastasis, while others contribute to the body’s defense against it. Moreover, auto-antibodies are of a polyclonal nature, which means that often several antibodies are involved in the response to a single tumor antigen. Dissection of these antibody specificities is now possible, allowing their identification at the genetic, structural, and epitope levels. In this review, we report the evidence available on the presence of auto-antibodies in the main cancer types and discuss some of the open issues that still need to be addressed by the research community. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Graphical abstract

13 pages, 600 KiB  
Review
The Emerging Role of Nerves and Glia in Colorectal Cancer
by Simone L. Schonkeren, Meike S. Thijssen, Nathalie Vaes, Werend Boesmans and Veerle Melotte
Cancers 2021, 13(1), 152; https://doi.org/10.3390/cancers13010152 - 05 Jan 2021
Cited by 26 | Viewed by 7171
Abstract
The role of the nervous system as a contributor in the tumor microenvironment has been recognized in different cancer types, including colorectal cancer (CRC). The gastrointestinal tract is a highly innervated organ system, which is not only innervated by the autonomic nervous system, [...] Read more.
The role of the nervous system as a contributor in the tumor microenvironment has been recognized in different cancer types, including colorectal cancer (CRC). The gastrointestinal tract is a highly innervated organ system, which is not only innervated by the autonomic nervous system, but also contains an extensive nervous system of its own; the enteric nervous system (ENS). The ENS is important for gut function and homeostasis by regulating processes such as fluid absorption, blood flow, and gut motility. Dysfunction of the ENS has been linked with multiple gastrointestinal diseases, such as Hirschsprung disease and inflammatory bowel disease, and even with neurodegenerative disorders. How the extrinsic and intrinsic innervation of the gut contributes to CRC is not fully understood, although a mutual relationship between cancer cells and nerves has been described. Nerves enhance cancer progression through the secretion of neurotransmitters and neuropeptides, and cancer cells are capable of stimulating nerve growth. This review summarizes and discusses the nervous system innervation of the gastrointestinal tract and how it can influence carcinogenesis, and vice versa. Lastly, the therapeutic potential of these novel insights is discussed. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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23 pages, 844 KiB  
Review
Tumor Microenvironment and Immunotherapy Response in Head and Neck Cancer
by Panagiota Economopoulou, Ioannis Kotsantis and Amanda Psyrri
Cancers 2020, 12(11), 3377; https://doi.org/10.3390/cancers12113377 - 15 Nov 2020
Cited by 33 | Viewed by 3348
Abstract
The tumor microenvironment (TME) encompasses cellular and non-cellular components which play an important role in tumor evolution, invasion, and metastasis. A complicated interplay between tumor cells and adjacent TME cells, such as stromal cells, immune cells, inflammatory cells, and cytokines, leads to severe [...] Read more.
The tumor microenvironment (TME) encompasses cellular and non-cellular components which play an important role in tumor evolution, invasion, and metastasis. A complicated interplay between tumor cells and adjacent TME cells, such as stromal cells, immune cells, inflammatory cells, and cytokines, leads to severe immunosuppression and the proliferation of cancer cells in several solid tumors. An immunosuppressive TME has a significant impact on treatment resistance and may guide response to immunotherapy. In head and neck cancer (HNC), immunotherapeutic drugs have been incorporated in everyday clinical practice. However, despite an exceptional rate of durable responses, only a low percentage of patients respond. In this review, we will focus on the complex interactions occurring in this dynamic system, the TME, which orchestrate key events that lead to tumor progression, immune escape, and resistance. Furthermore, we will summarize current clinical trials that depict the TME as a potential therapeutic target for improved patient selection. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Graphical abstract

16 pages, 285 KiB  
Review
Breast Cancer Heterogeneity and Response to Novel Therapeutics
by Mariona Baliu-Piqué, Atanasio Pandiella and Alberto Ocana
Cancers 2020, 12(11), 3271; https://doi.org/10.3390/cancers12113271 - 05 Nov 2020
Cited by 36 | Viewed by 4786
Abstract
Targeted cancer therapies against oncogenic drivers are actively being developed and tested in clinical trials. Targeting an oncogenic driver may only prove effective if the mutation is present in most tumoral cells. Therefore, highly heterogeneous tumors may be refractory to these therapies. This [...] Read more.
Targeted cancer therapies against oncogenic drivers are actively being developed and tested in clinical trials. Targeting an oncogenic driver may only prove effective if the mutation is present in most tumoral cells. Therefore, highly heterogeneous tumors may be refractory to these therapies. This makes tumor heterogeneity a major challenge in cancer therapy. Although heterogeneity has traditionally been attributed to genetic diversity within cancer cell populations, it is now widely recognized that human cancers are heterogeneous in almost all distinguishable phenotypic characteristics. Understanding the genetic variability and also the non-genetic influences of tumor heterogeneity will provide novel insights into how to reverse therapeutic resistance and improve cancer therapy. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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Graphical abstract

16 pages, 1109 KiB  
Review
Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy
by Gábor Valcz, Edit I. Buzás, Anna Sebestyén, Tibor Krenács, Zoltán Szállási, Péter Igaz and Béla Molnár
Cancers 2020, 12(8), 2324; https://doi.org/10.3390/cancers12082324 - 18 Aug 2020
Cited by 9 | Viewed by 3462
Abstract
Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual [...] Read more.
Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue “niche”, cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors. Full article
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
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