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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 17901

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Special Issue Editors

Prof. Dr. Benedetta Cinque

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Guest Editor

Department of Life, Health & Environmental Sciences, University of L’Aquila, Via Pompeo Spennati, Building Rita Levi Montalcini, Coppito, 67100 L’Aquila, Italy
Interests: inflammation; cyclooxygenase-2; tumor biology; cancer stem cells; probiotics; tissue repair

Dr. Paola Palumbo

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Guest Editor

Department of Life, Health & Environmental Sciences, University of L’Aquila, Via Pompeo Spennati, Building Rita Levi Montalcini, Coppito, 67100 L’Aquila, Italy
Interests: inflammation; glioma; cancer stem cells; tumor biology; cyclooxygenase-2; nitric oxide synthase 2
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Special Issue Information

Dear Colleagues,

Cancer stem cells (CSCs), also named tumor-initiating cells (TICs), are today the most complex challenge faced in cancer cure. An extensive body of research suggests that CSCs are the main drivers of tumor initiation and progression, and they are considered one of the main reasons behind cancer heterogeneity, recurrence, and resistance to conventional therapy. CSCs, also through the extracellular vesicles’ release, can interact in the tumor microenvironment with neighboring cells influencing resident cell fate by genetic reprogramming and maintaining some key stemness features, such as self-renewal and differentiation. The precise molecular mechanisms underlying the intricate scenario of CSCs are not yet fully understood. A deeper understanding of the CSCs’ molecular and biological features would certainly allow us to define new, targeted, and more effective therapeutic approaches to overcome cancer resistance and to improve survival rate and treatment response. This Special Issue will summarize the latest research (including original research articles as well as comprehensive reviews) on molecular and cellular mechanisms involved in CSC regulation including the intrinsic and extrinsic signaling pathways that underlie their stemness ability, maintenance, and resistance to conventional therapy.

We look forward to your contributions.

Prof. Dr. Benedetta Cinque
Prof. Dr. Paola Palumbo
Guest Editors

Manuscript Submission Information

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Keywords

cancer stem cells (CSCs)
resistance
self-renewal and maintenance
novel therapies
signaling pathways
CSCs’ metabolism

Published Papers (7 papers)

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Research

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18 pages, 2971 KiB

Open AccessArticle

Estrogen Receptor β4 Regulates Chemotherapy Resistance and Induces Cancer Stem Cells in Triple Negative Breast Cancer

by Ayesha Bano, Jessica H. Stevens, Paulomi S. Modi, Jan-Åke Gustafsson and Anders M. Strom

Int. J. Mol. Sci. 2023, 24(6), 5867; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065867 - 20 Mar 2023

Cited by 5 | Viewed by 2059

Abstract

Triple Negative Breast Cancer (TNBC) has the worst prognosis among all breast cancers, and survival in patients with recurrence is rarely beyond 12 months due to acquired resistance to chemotherapy, which is the standard of care for these patients. Our hypothesis is that Estrogen Receptor β1 (ERβ1) increases response to chemotherapy but is opposed by ERβ4, which it preferentially dimerizes with. The role of ERβ1 and ERβ4 in influencing chemotherapy sensitivity has never been studied before. CRISPR/CAS9 was used to truncate ERβ1 Ligand Binding Domain (LBD) and knock down the exon unique to ERβ4. We show that the truncated ERβ1 LBD in a variety of mutant p53 TNBC cell lines, where ERβ1 ligand dependent function was inactivated, had increased resistance to Paclitaxel, whereas the ERβ4 knockdown cell line was sensitized to Paclitaxel. We further show that ERβ1 LBD truncation, as well as treatment with ERβ1 antagonist 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a] pyrimidine (PHTPP), leads to increase in the drug efflux transporters. Hypoxia Inducible Factors (HIFs) activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells. Here we show that the ERβ1 and ERβ4 regulate these stem cell markers like SOX2, OCT4, and Nanog in an opposing manner; and we further show that this regulation is mediated by HIFs. We show the increase of cancer cell stemness due to ERβ1 LBD truncation is attenuated when HIF1/2α is knocked down by siRNA. Finally, we show an increase in the breast cancer stem cell population due to ERβ1 antagonist using both ALDEFLUOR^TM and SOX2/OCT4 response element (SORE6) reporters in SUM159 and MDA-MB-231 cell lines. Since most TNBC cancers are ERβ4 positive, while only a small proportion of TNBC patients are ERβ1 positive, we believe that simultaneous activation of ERβ1 with agonists and inactivation of ERβ4, in combination with paclitaxel, can be more efficacious and yield better outcome for chemotherapy resistant TNBC patients. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

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21 pages, 51118 KiB

Open AccessArticle

FOXM1-CD44 Signaling Is Critical for the Acquisition of Regorafenib Resistance in Human Liver Cancer Cells

by Kenly Wuputra, Pi-Jung Hsiao, Wen-Tsan Chang, Po-Hsuan Wu, Lin-Ann Chen, Jian-Wei Huang, Wen-Lung Su, Ya-Han Yang, Deng-Chyang Wu, Kazunari K. Yokoyama and Kung-Kai Kuo

Int. J. Mol. Sci. 2022, 23(14), 7782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147782 - 14 Jul 2022

Cited by 3 | Viewed by 1994

Abstract

Regorafenib is a multikinase inhibitor that was approved by the US Food and Drug administration in 2017. Cancer stem cells (CSCs) are a small subset of cancer-initiating cells that are thought to contribute to therapeutic resistance. The forkhead box protein M1 (FOXM1) plays an important role in the regulation of the stemness of CSCs and mediates resistance to chemotherapy. However, the relationship between FOXM1 and regorafenib resistance in liver cancer cells remains unknown. We found that regorafenib-resistant HepG2 clones overexpressed FOXM1 and various markers of CSCs. Patients with hepatocellular carcinoma also exhibited an upregulation of FOXM1 and resistance to regorafenib, which were correlated with a poor survival rate. We identified a close relationship between FOXM1 expression and regorafenib resistance, which was correlated with the survival of patients with hepatocellular carcinoma. Thus, a strategy that antagonizes FOXM1–CD44 signaling would enhance the therapeutic efficacy of regorafenib in these patients. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

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19 pages, 3411 KiB

Open AccessArticle

Effects of Ultra-Short Pulsed Electric Field Exposure on Glioblastoma Cells

by Arianna Casciati, Mirella Tanori, Isabella Gianlorenzi, Elena Rampazzo, Luca Persano, Giampietro Viola, Alice Cani, Silvia Bresolin, Carmela Marino, Mariateresa Mancuso and Caterina Merla

Int. J. Mol. Sci. 2022, 23(6), 3001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063001 - 10 Mar 2022

Cited by 7 | Viewed by 2798

Abstract

Glioblastoma multiforme (GBM) is the most common brain cancer in adults. GBM starts from a small fraction of poorly differentiated and aggressive cancer stem cells (CSCs) responsible for aberrant proliferation and invasion. Due to extreme tumor heterogeneity, actual therapies provide poor positive outcomes, and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary against GBM. Among emerging therapies, high intensity ultra-short pulsed electric fields (PEFs) are considered extremely promising and our previous results demonstrated the ability of a specific electric pulse protocol to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells and U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independent of CSC content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the ability to form new neurospheres and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stem-ness/differentiation genes. Our results confirm this physical stimulus as a promising treatment to destabilize GBM, opening up the possibility of developing effective PEF-mediated therapies. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

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17 pages, 5703 KiB

Open AccessArticle

CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer

by Lu Cao, Kim R. Bridle, Ritu Shrestha, Prashanth Prithviraj, Darrell H. G. Crawford and Aparna Jayachandran

Int. J. Mol. Sci. 2022, 23(3), 1565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031565 - 29 Jan 2022

Cited by 7 | Viewed by 3074

Abstract

Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract cancers with a dismal prognosis. Ongoing clinical trials are evaluating a few selected immune checkpoint inhibitors (ICIs) as monotherapy for the treatment of GBC patients. However, only a subset of patients benefits from these treatments. To improve ICI therapy response, molecular mechanisms that confer resistance to immune checkpoint (IC) blockade needs to be explored. Epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs) have been implicated as key processes that confer ICI treatment resistance. However, in GBC the EMT-CSC-IC axis has not yet been clearly elucidated. This study aims to examine the aberrant expression of ICs associated with CSC and EMT. We successfully enriched CSCs by utilizing a 3-dimensional culture system and established a reversible EMT model with human GBC NOZ cell line. Notably, ICs CD73 and PD-L1 were closely associated with both CSC and EMT phenotypes. Knockdown of CD73 or PD-L1 reduced the proliferative and motile abilities of both adherent monolayers and anchorage-free spheroids. In conclusion, blocking CD73 and PD-L1 offer a promising therapeutic strategy for targeting highly aggressive populations with CSC and EMT phenotype to improve GBC patient prognosis. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

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Review

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17 pages, 351 KiB

Open AccessReview

Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells

by Loredana G. Marcu, Leyla Moghaddasi and Eva Bezak

Int. J. Mol. Sci. 2023, 24(2), 1524; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021524 - 12 Jan 2023

Cited by 2 | Viewed by 1476

Abstract

Cancer stem cells are known to play a key role in tumour development, proliferation, and metastases. Their unique properties confer resistance to therapy, often leading to treatment failure. It is believed that research into the identification, targeting, and eradication of these cells can revolutionise oncological treatment. Based on the principle that what cannot be seen, cannot be targeted, a primary step in cancer management is the identification of these cells. The current review aims to encompass the state-of-the-art functional imaging techniques that enable the identification of cancer stem cells via various pathways and mechanisms. The paper presents in vivo molecular techniques that are currently available or await clinical implementation. Challenges and future prospects are highlighted to open new research avenues in cancer stem cell imaging. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

14 pages, 2316 KiB

Open AccessReview

The Role of Cancer Stem Cells and Their Extracellular Vesicles in the Modulation of the Antitumor Immunity

by Daria S. Chulpanova, Albert A. Rizvanov and Valeriya V. Solovyeva

Int. J. Mol. Sci. 2023, 24(1), 395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010395 - 26 Dec 2022

Cited by 3 | Viewed by 2680

Abstract

Cancer stem cells (CSCs) are a population of tumor cells that share similar properties to normal stem cells. CSCs are able to promote tumor progression and recurrence due to their resistance to chemotherapy and ability to stimulate angiogenesis and differentiate into non-CSCs. Cancer stem cells can also create a significant immunosuppressive environment around themselves by suppressing the activity of effector immune cells and recruiting cells that support tumor escape from immune response. The immunosuppressive effect of CSCs can be mediated by receptors located on their surface, as well as by secreted molecules, which transfer immunosuppressive signals to the cells of tumor microenvironment. In this article, the ability of CSCs to regulate the antitumor immune response and a contribution of CSC-derived EVs into the avoidance of the immune response are discussed. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

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19 pages, 1306 KiB

Open AccessReview

Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation

by Xiaona Fang, Qian Yan, Shan Liu and Xin-Yuan Guan

Int. J. Mol. Sci. 2022, 23(20), 12327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012327 - 14 Oct 2022

Cited by 13 | Viewed by 2987

Abstract

Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients. Full article

(This article belongs to the Special Issue Molecular Research on Cancer Stem Cell)

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