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Biomolecules
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Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem...
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Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological and Bio- Materials".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 17080

Special Issue Editors

Dr. Shih-Chieh Hung

E-Mail Website
Guest Editor
Director, Drug Development Center, China Mdical University; Distingushed Professor, Institute of New Drug Development, China Medical University; Director, Integrative Stem Cell Center, China Medical University Hospital, Taichung, Taiwan
Interests: basic research; translational medicine; clinical trial of using mesenchymal stem cells; nanotechnology in theranostics; cancer stem cells; organoid culture
Dr. Micol Eleonora Fiori

E-Mail Website
Guest Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
Interests: colorectal cancer; cancer stem cells; metastases; tumor microenvironment; tumor-stroma interaction; cancer associated fibroblasts; spheroids/3D cultures; RNA/non-coding RNA
Dr. Sara Vitale

E-Mail Website
Guest Editor
Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
Interests: neoplastic stem cells; colorectal neoplasms; cancer stem cells

Special Issue Information

Dear Colleagues, 

Cancer stem cells (CSCs) are defined as a subpopulation of multipotent cells with unique properties of self-renewal, long-term maintenance, and plasticity. CSCs are able to differentiate, switching between CSC and non-CSC states, in a dynamic crosstalk with components of the tumor microenvironment. First described in hematological cancers, CSCs have been identified at varying frequencies in multiple solid tumors. CSCs are responsible for cancer initiation and progression, metastatic spread, drug resistance, and tumor relapse. Thus, efficient targeting and eradication of CSCs are necessary for effective and durable cancer therapies. These cells exhibit multiple therapeutic resistance, including immune evasion, quiescence, enhanced drug-efflux pumps, DNA repair, and ROS protection. The identification of key players responsible for their robustness and resilience is critical for the development of novel therapeutic strategies able to eradicate cancer. Advanced technologies are currently applied to cancer research to dissect molecular roots of cancer in a patient-specific resolution. Here, we invite authors to contribute with research or review articles describing recent progress in CSC molecular characterization and therapeutic targeting.

The focus of this Special Issue includes but is not limited to the following topics:

- CSC molecular profiling/specific gene-expression signatures;

- CSC epigenetic regulation;

- Identification/study of signaling pathways activated in CSCs;

- Identification and in vivo tracing of CSCs;

- Novel therapeutic strategies selectively targeting cancer stem cells, their plasticity, and drug resistance.

Cutting-edge studies on in vitro models (3D cultures) derived from human primary samples and/or mouse models are also highly welcome.

Dr. Shih-Chieh Hung
Dr. Micol Eleonora Fiori
Dr. Sara Vitale
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. Biomolecules is an international peer-reviewed open access monthly 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 2700 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

  • Cancer stem cells
  • Metastasis
  • Tumor microenvironment
  • CSC metabolism
  • CSCs epigenetic regulation

Published Papers (5 papers)

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Research

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20 pages, 2548 KiB  
Article
Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
by Virve Cavallucci, Ivana Palucci, Marco Fidaleo, Antonella Mercuri, Letizia Masi, Valeria Emoli, Giada Bianchetti, Micol Eleonora Fiori, Gilad Bachrach, Franco Scaldaferri, Giuseppe Maulucci, Giovanni Delogu and Giovambattista Pani
Biomolecules 2022, 12(9), 1256; https://doi.org/10.3390/biom12091256 - 07 Sep 2022
Cited by 8 | Viewed by 3248
Abstract
Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and [...] Read more.
Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and a poor clinical outcome; however, the primary cellular and/or microenvironmental targets of this agent remain elusive. We report here that Fn directly targets putative colorectal cancer stem cells (CR-CSCs), a tumor cell subset endowed with cancer re-initiating capacity after surgery and chemotherapy. A patient-derived CSC line, highly enriched (70%) for the stem marker CD133, was expanded as tumor spheroids, dissociated, and exposed in vitro to varying amounts (range 100–500 MOI) of Fn. We found that Fn stably adheres to CSCs, likely by multiple interactions involving the tumor-associated Gal-GalNac disaccharide and the Fn-docking protein CEA-family cell adhesion molecule 1 (CEACAM-1), robustly expressed on CSCs. Importantly, Fn elicited innate immune responses in CSCs and triggered a growth factor-like, protein tyrosine phosphorylation cascade largely dependent on CEACAM-1 and culminating in the activation of p42/44 MAP kinase. Thus, the direct stimulation of CSCs by Fn may contribute to microbiota-driven colorectal carcinogenesis and represent a target for innovative therapies. Full article
(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)
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12 pages, 2374 KiB  
Article
Alanine–Glyoxylate Aminotransferase Sustains Cancer Stemness Properties through the Upregulation of SOX2 and OCT4 in Hepatocellular Carcinoma Cells
by Peng Ye, Xiaoxia Chi, Xiuwen Yan, Fangqin Wu, Zhigang Liang and Wen-Hao Yang
Biomolecules 2022, 12(5), 668; https://doi.org/10.3390/biom12050668 - 05 May 2022
Cited by 2 | Viewed by 2517
Abstract
Liver cancer stem cells (LCSCs) are a small subset of oncogenic cells with a self-renewal ability and drug resistance, and they promote the recurrence and metastasis of hepatocellular carcinoma (HCC). However, the mechanisms regulating LCSCs have not been fully explored. By enriching LCSCs [...] Read more.
Liver cancer stem cells (LCSCs) are a small subset of oncogenic cells with a self-renewal ability and drug resistance, and they promote the recurrence and metastasis of hepatocellular carcinoma (HCC). However, the mechanisms regulating LCSCs have not been fully explored. By enriching LCSCs from spheroid cultures and performing transcriptomic analysis, we determined that alanine–glyoxylate aminotransferase (AGXT), which participates in the metabolism of serine and glycine, was significantly upregulated in spheroid cultures, and its function in LCSCs remains unknown. Through the exogenous overexpression or short hairpin RNA knockdown of AGXT in HCC cells, we observed that changes in the AGXT level did not affect the spheroid ability and population of LCSCs. The knockdown of AGXT in LCSCs reduced the number of spheroids and the population of LCSCs; this implies that AGXT is required for the maintenance of cancer stemness rather than as a driver of LCSCs. Mechanistically, AGXT may sustain the self-renewal potential of LCSCs by upregulating the expression of SRY-box transcription factor 2 (SOX2) and octamer-binding transcription factor 4 (OCT4), two well-known master regulators of cancer stemness. Taken together, our study demonstrates the role of AGXT in supporting LCSCs; thus, AGXT merits further exploration. Full article
(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)
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14 pages, 2437 KiB  
Article
Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
by Chen-Chi Liu, Hsin-Hsien Li, Jiun-Han Lin, Ming-Chen Chiang, Tien-Wei Hsu, Anna Fen-Yau Li, David Hung-Tsang Yen, Han-Shui Hsu and Shih-Chieh Hung
Biomolecules 2022, 12(1), 48; https://doi.org/10.3390/biom12010048 - 29 Dec 2021
Cited by 16 | Viewed by 3135
Abstract
Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we [...] Read more.
Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma. Full article
(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)
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Review

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35 pages, 1396 KiB  
Review
Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells
by Shahang Luo, Guanghui Yang, Peng Ye, Nengqi Cao, Xiaoxia Chi, Wen-Hao Yang and Xiuwen Yan
Biomolecules 2022, 12(6), 850; https://doi.org/10.3390/biom12060850 - 19 Jun 2022
Cited by 17 | Viewed by 4333
Abstract
Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). [...] Read more.
Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC–TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk. Full article
(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)
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19 pages, 814 KiB  
Review
Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy
by Melania Lo Iacono, Chiara Modica, Gaetana Porcelli, Ornella Roberta Brancato, Giampaolo Muratore, Paola Bianca, Miriam Gaggianesi, Alice Turdo, Veronica Veschi, Matilde Todaro, Simone Di Franco and Giorgio Stassi
Biomolecules 2022, 12(5), 702; https://doi.org/10.3390/biom12050702 - 14 May 2022
Cited by 3 | Viewed by 2889
Abstract
The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells [...] Read more.
The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. In this review, we highlight the mechanisms underlying the bidirectional crosstalk among CAAs, CSCs, and stromal cells. Moreover, we focus on the recent advances in the therapeutic targeting of adipocyte-released factors as an innovative strategy to counteract cancer progression. Full article
(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)
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