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Cancer Metastases: Impact of Epithelial-Mesenchymal Transition, Stem Cell and Microenvironment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 10799

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Special Issue Editors

Dr. Nadezhda V. Cherdyntseva

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Guest Editor

Cancer Research Institute, Tomsk National Research Medical Center, 634050 Tomsk, Russia
Interests: anticancer therapy; immunology; cancer initiation and progression; breast cancer; molecular genetic research

Dr. Evgeny L. Choynzonov

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Guest Editor

Tomsk National Research Medical Center of the Russian Academy of Sciences, Cancer Research Institute, 5 Kooperativny Street, 634009 Tomsk, Russia
Interests: head and neck cancers; radiation therapy; carcinogenesis; molecular markers

Dr. Liubov A. Tashireva

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Guest Editor

Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciencesd, Tomsk, Russia
Interests: breast cancer; metastasis; tumor microenvironment; genetic heterogeneity

Special Issue Information

Dear Colleagues,

From the standpoint of modern knowledge, the close relationship of Epithelial-to-mesenchymal transition (EMT) programs and stemness in neoplastic epithelial tissues at different stages of the metastatic cascade, including the primary tumor, circulating tumor cells (CTC), and distant sites of metastasis (disseminated and dormant tumor cells), is becoming increasingly evident. However, there is no clear understanding of the biological mechanisms underlying the association between EMT programs and stemness. What signals are crucial for inducing or maintaining stemness? What are the conditions and mechanisms for the development of EMT without synchronous acquiring of stemness features? New data on the differences between EMT induced by various transcription factors and their relationship to stemness are also relevant. Currently, there are no universal and appropriate markers that allow us to determine the discrete phenotypes of EMT and stemness of tumor cells, which differ in the expression of transcription factors and protein markers. The relevant question is - what are the ratios of these states in primary tumor cells, CTCs, and disseminated and dormant cells? Another question is - how are they associated with hematogenous metastasis? Research in these fields will undoubtedly contribute to the search and development of new clinically significant markers and targets for the next generation of cancer therapy. The special issue will contain original research and review articles devoted to studying the phenomenon of plasticity in EMT programs and stemness and identification of significant markers for the differentiation of the EMT phenotypes and cell stemness in the primary tumor, circulation, and metastasis sites.

Topics of this Special Issue include, but are not limited to:

Initiation and maintenance of EMT and stemness, including the primary tumor, circulating tumor cells, distant sites of metastasis (disseminated and dormant tumor cells)
Transcription factors and signaling pathways of EMT and stemness at different stages of the metastatic cascade
Expression and functional proteomic markers of various EMT and stem phenotypes in tumor cells
Heterogeneity of the phenotypic manifestations of EMT and stem cells, including the primary tumor cells, circulating and disseminated and dormant tumor cells
The role of the tumor microenvironment in the regulation of EMT and stemness of tumor cells
New methodological approaches to the determination of EMT and stem properties of tumor cells, including primary tumor, circulating tumor cells, distant metastasis sites (disseminated and dormant tumor cells)
Models for studying EMT programs and stemness in neoplastic epithelial tissues

Dr. Nadezhda V. Cherdyntseva
Dr. Evgeny L. Choynzonov
Dr. Liubov A. Tashireva
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

hematogenic metastasis
epithelial-to-mesenchymal transition
tumor stem cells
circulating tumor cells
disseminated tumor cells
microenvironment
tumor cell transcriptomics

Published Papers (5 papers)

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Research

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20 pages, 4007 KiB

Open AccessArticle

Inactivation of PTEN and ZFHX3 in Mammary Epithelial Cells Alters Patterns of Collective Cell Migration

by Ali Dayoub, Artem I. Fokin, Maria E. Lomakina, John James, Marina Plays, Tom Jacquin, Nikita M. Novikov, Rostislav S. Vorobyov, Anastasia A. Schegoleva, Karina D. Rysenkova, Julia Gaboriaud, Sergey V. Leonov, Evgeny V. Denisov, Alexis M. Gautreau and Antonina Y. Alexandrova

Int. J. Mol. Sci. 2023, 24(1), 313; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010313 - 24 Dec 2022

Cited by 2 | Viewed by 1775

Abstract

Whole exome sequencing of invasive mammary carcinomas revealed the association of mutations in PTEN and ZFHX3 tumor suppressor genes (TSGs). We generated single and combined PTEN and ZFHX3 knock-outs (KOs) in the immortalized mammary epithelial cell line MCF10A to study the role of these genes and their potential synergy in migration regulation. Inactivation of PTEN, but not ZFHX3, induced the formation of large colonies in soft agar. ZFHX3 inactivation in PTEN KO, however, increased colony numbers and normalized their size. Cell migration was affected in different ways upon PTEN and ZFHX3 KO. Inactivation of PTEN enhanced coordinated cell motility and thus, the collective migration of epithelial islets and wound healing. In contrast, ZFHX3 knockout resulted in the acquisition of uncoordinated cell movement associated with the appearance of immature adhesive junctions (AJs) and the increased expression of the mesenchymal marker vimentin. Inactivation of the two TSGs thus induces different stages of partial epithelial-to-mesenchymal transitions (EMT). Upon double KO (DKO), cells displayed still another motile state, characterized by a decreased coordination in collective migration and high levels of vimentin but a restoration of mature linear AJs. This study illustrates the plasticity of migration modes of mammary cells transformed by a combination of cancer-associated genes. Full article

(This article belongs to the Special Issue Cancer Metastases: Impact of Epithelial-Mesenchymal Transition, Stem Cell and Microenvironment)

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14 pages, 2676 KiB

Open AccessArticle

The Novel Association of Early Apoptotic Circulating Tumor Cells with Treatment Outcomes in Breast Cancer Patients

by Evgeniya S. Grigoryeva, Liubov A. Tashireva, Vladimir V. Alifanov, Olga E. Savelieva, Sergey V. Vtorushin, Marina V. Zavyalova, Nadezhda V. Cherdyntseva and Vladimir M. Perelmuter

Int. J. Mol. Sci. 2022, 23(16), 9475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169475 - 22 Aug 2022

Cited by 5 | Viewed by 1486

Abstract

Stemness and epithelial–mesenchymal plasticity are widely studied in the circulating tumor cells of breast cancer patients because the roles of both processes in tumor progression are well established. An important property that should be taken into account is the ability of CTCs to disseminate, particularly the viability and apoptotic states of circulating tumor cells (CTCs). Recent data demonstrate that apoptosis reversal promotes the formation of stem-like tumor cells with pronounced potential for dissemination. Our study focused on the association between different apoptotic states of CTCs with short- and long-term treatment outcomes. We evaluated the association of viable CTCs, CTCs with early features of apoptosis, and end-stage apoptosis/necrosis CTCs with clinicopathological parameters of breast cancer patients. We found that the proportion of circulating tumor cells with features of early apoptosis is a perspective prognosticator of metastasis-free survival, which also correlates with the neoadjuvant chemotherapy response in breast cancer patients. Moreover, we establish that apoptotic CTCs are associated with the poor response to neoadjuvant chemotherapy, and metastasis-free survival expressed at least two stemness markers, CD44 and CD133. Full article

(This article belongs to the Special Issue Cancer Metastases: Impact of Epithelial-Mesenchymal Transition, Stem Cell and Microenvironment)

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15 pages, 4285 KiB

Open AccessArticle

PGC1α Cooperates with FOXA1 to Regulate Epithelial Mesenchymal Transition through the TCF4-TWIST1

by Xue-Quan Fang, Mingyu Lee, Woo-Jin Lim, Seonghoon Lee, Chang-Hoon Lim and Ji-Hong Lim

Int. J. Mol. Sci. 2022, 23(15), 8247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158247 - 26 Jul 2022

Cited by 4 | Viewed by 2076

Abstract

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a critical transcriptional coactivator that maintains metabolic homeostasis and energy expenditure by cooperating with various transcription factors. Recent studies have shown that PGC1α deficiency promotes lung cancer metastasis to the bone through activation of TCF4 and TWIST1-mediated epithelial–mesenchymal transition (EMT), which is suppressed by the inhibitor of DNA binding 1 (ID1); however, it is not clear which transcription factor participates in PGC1α-mediated EMT and lung cancer metastasis. Here, we identified forkhead box A1 (FOXA1) as a potential transcription factor that coordinates with PGC1α and ID1 for EMT gene expression using transcriptome analysis. Cooperation between FOXA1 and PGC1α inhibits promoter occupancy of TCF4 and TWIST1 on CDH1 and CDH2 proximal promoter regions due to increased ID1, consequently regulating the expression of EMT-related genes such as CDH1, CDH2, VIM, and PTHLH. Transforming growth factor beta 1 (TGFβ1), a major EMT-promoting factor, was found to decrease ID1 due to the suppression of FOXA1 and PGC1α. In addition, ectopic expression of ID1, FOXA1, and PGC1α reversed TGFβ1-induced EMT gene expression. Our findings suggest that FOXA1- and PGC1α-mediated ID1 expression involves EMT by suppressing TCF4 and TWIST1 in response to TGFβ1. Taken together, this transcriptional framework is a promising molecular target for the development of therapeutic strategies for lung cancer metastasis. Full article

(This article belongs to the Special Issue Cancer Metastases: Impact of Epithelial-Mesenchymal Transition, Stem Cell and Microenvironment)

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21 pages, 4323 KiB

Open AccessArticle

The Diminishment of Novel Endometrial Carcinoma-Derived Stem-like Cells by Targeting Mitochondrial Bioenergetics and MYC

by Laureen P. Helweg, Beatrice A. Windmöller, Leonie Burghardt, Jonathan Storm, Christine Förster, Nils Wethkamp, Ludwig Wilkens, Barbara Kaltschmidt, Constanze Banz-Jansen and Christian Kaltschmidt

Int. J. Mol. Sci. 2022, 23(5), 2426; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052426 - 22 Feb 2022

Cited by 1 | Viewed by 2152

Abstract

Cancer stem cells (CSCs) are a small subpopulation of tumor cells harboring properties that include self-renewal, multi-lineage differentiation, tumor reconstitution, drug resistance and invasiveness, making them key players in tumor relapse. In the present paper, we develop new CSC models and analyze the molecular pathways involved in survival to identify targets for the establishment of novel therapies. Endometrial carcinoma-derived stem-like cells (ECSCs) were isolated from carcinogenic gynecological tissue and analyzed regarding their expression of prominent CSC markers. Further, they were treated with the MYC-signaling inhibitor KJ-Pyr-9, chemotherapeutic agent carboplatin and type II diabetes medication metformin. ECSC populations express common CSC markers, such as Prominin-1 and CD44 antigen as well as epithelial-to-mesenchymal transition markers, Twist, Snail and Slug, and exhibit the ability to form free-floating spheres. The inhibition of MYC signaling and treatment with carboplatin as well as metformin significantly reduced the cell survival of ECSC-like cells. Further, treatment with metformin significantly decreased the mitochondrial membrane potential of ECSC-like cells, while the extracellular lactate concentration was increased. The established ECSC-like populations represent promising in vitro models to further study the contribution of ECSCs to endometrial carcinogenesis. Targeting MYC signaling as well as mitochondrial bioenergetics has shown promising results in the diminishment of ECSCs, although molecular signaling pathways need further investigations. Full article

(This article belongs to the Special Issue Cancer Metastases: Impact of Epithelial-Mesenchymal Transition, Stem Cell and Microenvironment)

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Review

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16 pages, 2269 KiB

Open AccessReview

The Significance of Cancer Stem Cells and Epithelial–Mesenchymal Transition in Metastasis and Anti-Cancer Therapy

by Lili Liang and Andreas M. Kaufmann

Int. J. Mol. Sci. 2023, 24(3), 2555; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032555 - 29 Jan 2023

Cited by 8 | Viewed by 2514

Abstract

Cancer stem cells (CSCs) have been identified and characterized in both hematopoietic and solid tumors. Their existence was first predicted by Virchow and Cohnheim in the 1870s. Later, many studies showed that CSCs can be identified and isolated by their expression of specific cell markers. The significance of CSCs with respect to tumor biology and anti-cancer treatment lies in their ability to maintain quiescence with very slow proliferation, indefinite self-renewal, differentiation, and trans-differentiation such as epithelial–mesenchymal transition (EMT) and its reverse process mesenchymal–epithelial transition (MET). The ability for detachment, migration, extra- and intravasation, invasion and thereby of completing all necessary steps of the metastatic cascade highlights their significance for metastasis. CSCs comprise the cancer cell populations responsible for tumor growth, resistance to therapies and cancer metastasis. In this review, the history of the CSC theory, their identification and characterization and their biology are described. The contribution of the CSC ability to undergo EMT for cancer metastasis is discussed. Recently, novel strategies for drug development have focused on the elimination of the CSCs specifically. The unique functional and molecular properties of CSCs are discussed as possible therapeutic vulnerabilities for the development of novel anti-metastasis treatments. Prospectively, this may provide precise personalized anti-cancer treatments with improved therapeutic efficiency with fewer side effects and leading to better prognosis. Full article

(This article belongs to the Special Issue Cancer Metastases: Impact of Epithelial-Mesenchymal Transition, Stem Cell and Microenvironment)

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