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New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (14 May 2020) | Viewed by 70219

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Dr. Ugo Cavallaro

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Guest Editor

Unit of Gynecological Oncology Research, European Institute of Oncology, Via G. Ripamonti 435, 20141 Milan, Italy
Interests: ovarian cancer; cancer stem cells; tumor microenvrironment; tumor angiogenesis; cell adhesion molecules

Dr. Marco Giordano

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Guest Editor

European Inst Oncol, Unit Gynecol Oncol Res, Via G Ripamonti 435, I-20141 Milan, Italy
Interests: cancer stem cells; ovarian cancer; immune escape; signalling; cancer models

Special Issue Information

Dear Colleagues,

The cancer stem cell (CSC) paradigm represents one of the most prominent breakthroughs of the last decades in tumor biology. CSCs are broadly defined as a subpopulation of tumor cells that, besides sharing some functional features with normal stem cells (self-renewal, low cycling rate and differentiation capacity), are able to drive tumor initiation, to rebuild the heterogeneity of the original tumor, to evade the immune system and to escape conventional treatments such as chemo- and radiotherapy. In light of these properties, CSCs have been implicated in tumor metastasis and recurrence. Nevertheless, the biological characteristics of CSCs, their molecular profile, their contribution to cancer progression, and even their existence, remain matters of intense debate and controversy among tumor biologists. The difficulty in achieving a better definition of CSC biology may actually be explained by the plasticity of such a cell subpopulation. Indeed, the emerging view is that CSCs represent a dynamic “state” of tumor cells that can acquire stemness-related properties under specific circumstances, rather than referring to a well-defined group of cells.

Independent of their origin, it is clear that designing novel antitumor treatments based on the eradication of CSCs will only be possible upon unraveling the biological mechanisms that underlie their pathogenic role in tumor progression and therapy resistance. The Special Issue on “New aspects of cancer stem cell biology: implications for innovative therapies” aims at highlighting recent insights into CSC features that can make them an attractive target for novel therapeutic strategies.

Dr. Ugo Cavallaro
Dr. Marco Giordano
Guest Editors

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Keywords

cancer stem cells
tumor-initiating cells
drug resistance
novel therapies
metastasis
tumor recurrence
biomarkers
signaling pathways
metabolism
CSC-based models

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Published Papers (11 papers)

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Research

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13 pages, 1812 KiB

Open AccessArticle

Patient-Derived Colorectal Cancer Organoids Upregulate Revival Stem Cell Marker Genes following Chemotherapeutic Treatment

by Rebekah M. Engel, Wing Hei Chan, David Nickless, Sara Hlavca, Elizabeth Richards, Genevieve Kerr, Karen Oliva, Paul J. McMurrick, Thierry Jardé and Helen E. Abud

J. Clin. Med. 2020, 9(1), 128; https://doi.org/10.3390/jcm9010128 - 2 Jan 2020

Cited by 41 | Viewed by 8201

Abstract

Colorectal cancer stem cells have been proposed to drive disease progression, tumour recurrence and chemoresistance. However, studies ablating leucine rich repeat containing G protein-coupled receptor 5 (LGR5)-positive stem cells have shown that they are rapidly replenished in primary tumours. Following injury in normal tissue, LGR5+ stem cells are replaced by a newly defined, transient population of revival stem cells. We investigated whether markers of the revival stem cell population are present in colorectal tumours and how this signature relates to chemoresistance. We examined the expression of different stem cell markers in a cohort of patient-derived colorectal cancer organoids and correlated expression with sensitivity to 5-fluorouracil (5-FU) treatment. Our findings revealed that there was inter-tumour variability in the expression of stem cell markers. Clusterin (CLU), a marker of the revival stem cell population, was significantly enriched following 5-FU treatment and expression correlated with the level of drug resistance. Patient outcome data revealed that CLU expression is associated with both lower patient survival and an increase in disease recurrence. This suggests that CLU is a marker of drug resistance and may identify cells that drive colorectal cancer progression. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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16 pages, 2950 KiB

Open AccessArticle

Lipid Droplets Define a Sub-Population of Breast Cancer Stem Cells

by Benjamin J. Hershey, Roberta Vazzana, Débora L. Joppi and Kristina M. Havas

J. Clin. Med. 2020, 9(1), 87; https://doi.org/10.3390/jcm9010087 - 29 Dec 2019

Cited by 46 | Viewed by 6203

Abstract

Tumor recurrence is now the leading cause of breast cancer-related death. These recurrences are believed to arise from residual cancer stem cells that survive initial therapeutic intervention. Therefore, a comprehensive understanding of cancer stem cell biology is needed to generate more effective therapies. Here we investigate the association between dysregulation of lipid metabolism and breast cancer stem cells. Focusing specifically on lipid droplets, we found that the lipid droplet number correlates with stemness in a panel of breast cell lines. Using a flow cytometry-based method developed for this study, we establish a means to isolate cells with augmented lipid droplet loads from total populations and show that they are enriched in cancer stem cells. Furthermore, pharmacological targeting of fatty acid metabolism reveals a metabolic addiction in a subset of cell lines. Our results highlight a key role for the lipid metabolism in the maintenance of the breast cancer stem cell pool, and as such, suggest it as a potential therapeutic target. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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16 pages, 2848 KiB

Open AccessArticle

B4GALT1 Is a New Candidate to Maintain the Stemness of Lung Cancer Stem Cells

by Claudia De Vitis, Giacomo Corleone, Valentina Salvati, Francesca Ascenzi, Matteo Pallocca, Francesca De Nicola, Maurizio Fanciulli, Simona di Martino, Sara Bruschini, Christian Napoli, Alberto Ricci, Massimiliano Bassi, Federico Venuta, Erino Angelo Rendina, Gennaro Ciliberto and Rita Mancini

J. Clin. Med. 2019, 8(11), 1928; https://doi.org/10.3390/jcm8111928 - 9 Nov 2019

Cited by 16 | Viewed by 5166

Abstract

Background: According to the cancer stem cells (CSCs) hypothesis, a population of cancer cells with stem cell properties is responsible for tumor propagation, drug resistance, and disease recurrence. Study of the mechanisms responsible for lung CSCs propagation is expected to provide better understanding of cancer biology and new opportunities for therapy. Methods: The Lung Adenocarcinoma (LUAD) NCI-H460 cell line was grown either as 2D or as 3D cultures. Transcriptomic and genome-wide chromatin accessibility studies of 2D vs. 3D cultures were carried out using RNA-sequencing and Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq), respectively. Reverse transcription polymerase chain reaction (RT-PCR) was also carried out on RNA extracted from primary cultures derived from malignant pleural effusions to validate RNA-seq results. Results: RNA-seq and ATAC-seq data disentangled transcriptional and genome accessibility variability of 3D vs. 2D cultures in NCI-H460 cells. The examination of genomic landscape of genes upregulated in 3D vs. 2D cultures led to the identification of 2D cultures led to the identification of Beta-1,4-galactosyltranferase 1 (B4GALT1) as the top candidate. B4GALT1 as the top candidate. B4GALT1 was validated as a stemness factor, since its silencing caused strong inhibition of 3D spheroid formation. Conclusion: Combined transcriptomic and chromatin accessibility study of 3D vs. 2D LUAD cultures led to the identification of B4GALT1 as a new factor involved in the propagation and maintenance of LUAD CSCs. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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14 pages, 1474 KiB

Open AccessArticle

SOX2 Expression Is an Independent Predictor of Oral Cancer Progression

by Juan C. de Vicente, Paula Donate-Pérez del Molino, Juan P. Rodrigo, Eva Allonca, Francisco Hermida-Prado, Rocío Granda-Díaz, Tania Rodríguez Santamarta and Juana M. García-Pedrero

J. Clin. Med. 2019, 8(10), 1744; https://doi.org/10.3390/jcm8101744 - 21 Oct 2019

Cited by 35 | Viewed by 4131

Abstract

Potentially malignant oral lesions, mainly leukoplakia, are common. Malignant transformation varies widely, even in the absence of histological features such as dysplasia. Hence, there is a need for novel biomarker-based systems to more accurately predict the risk of cancer progression. The pluripotency transcription factor SOX2 is frequently overexpressed in cancers, including oral squamous cell carcinoma (OSCC), thereby providing a link between malignancy and stemness. This study investigates the clinical relevance of SOX2 protein expression in early stages of oral carcinogenesis as a cancer risk biomarker, and also its impact on prognosis and disease outcome at late stages of OSCC progression. SOX2 expression was evaluated by immunohistochemistry in 55 patients with oral epithelial dysplasia, and in 125 patients with OSCC, and correlated with clinicopathological data and outcomes. Nuclear SOX2 expression was detected in four (7%) cases of oral epithelial dysplasia, using a cut-off of 10% stained nuclei, and in 16 (29%) cases when any positive nuclei was evaluated. Univariate analysis showed that SOX2 expression and histopathological grading were significantly associated with oral cancer risk; and both were found to be significant independent predictors in the multivariate analysis. Nuclear SOX2 expression was also found in 49 (39%) OSCC cases, was more frequent in early tumor stages and N0 cases, and was associated with a better survival. In conclusion, SOX2 expression emerges as an independent predictor of oral cancer risk in patients with oral leukoplakia. These findings underscore the relevant role of SOX2 in early oral tumorigenesis rather than in tumor progression. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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17 pages, 3178 KiB

Open AccessArticle

The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042

by Francisco Hermida-Prado, M. Ángeles Villaronga, Rocío Granda-Díaz, Nagore del-Río-Ibisate, Laura Santos, Maria Ana Hermosilla, Patricia Oro, Eva Allonca, Jackeline Agorreta, Irati Garmendia, Juan Tornín, Jhudit Perez-Escuredo, Rocío Fuente, Luis M. Montuenga, Francisco Morís, Juan P. Rodrigo, René Rodríguez and Juana M. García-Pedrero

J. Clin. Med. 2019, 8(8), 1157; https://doi.org/10.3390/jcm8081157 - 2 Aug 2019

Cited by 18 | Viewed by 4841

Abstract

The frequent dysregulation of SRC family kinases (SFK) in multiple cancers prompted various inhibitors to be actively tested in preclinical and clinical trials. Disappointingly, dasatinib and saracatinib failed to demonstrate monotherapeutic efficacy in patients with head and neck squamous cell carcinomas (HNSCC). Deeper functional and mechanistic knowledge of the actions of these drugs is therefore needed to improve clinical outcome and to develop more efficient combinational strategies. Even though the SFK inhibitors dasatinib and saracatinib robustly blocked cell migration and invasion in HNSCC cell lines, this study unveils undesirable stem cell-promoting functions that could explain the lack of clinical efficacy in HNSCC patients. These deleterious effects were targeted by the mithramycin analog EC-8042 that efficiently eliminated cancer stem cells (CSC)-enriched tumorsphere cultures as well as tumor bulk cells and demonstrated potent antitumor activity in vivo. Furthermore, combination treatment of dasatinib with EC-8042 provided favorable complementary anti-proliferative, anti-invasive, and anti-CSC functions without any noticeable adverse interactions of both agents. These findings strongly support combinational strategies with EC-8042 for clinical testing in HNSCC patients. These data may have implications on ongoing dasatinib-based trials. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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15 pages, 1209 KiB

Open AccessArticle

Stem Cells Inhibition by Bevacizumab in Combination with Neoadjuvant Chemotherapy for Breast Cancer

by Renaud Sabatier, Emmanuelle Charafe-Jauffret, Jean-Yves Pierga, Hervé Curé, Eric Lambaudie, Dominique Genre, Gilles Houvenaeghel, Patrice Viens, Christophe Ginestier, François Bertucci, Patrick Sfumato, Jean-Marc Extra and Anthony Gonçalves

J. Clin. Med. 2019, 8(5), 612; https://doi.org/10.3390/jcm8050612 - 6 May 2019

Cited by 8 | Viewed by 3308

Abstract

Preclinical works have suggested cytotoxic chemotherapies may increase the number of cancer stem cells (CSC) whereas angiogenesis inhibition may decrease CSC proliferation. We developed a proof of concept clinical trial to explore bevacizumab activity on breast CSC. Breast cancer patients requiring preoperative chemotherapy were included in this open-label, randomized, prospective, multicenter phase II trial. All received FEC-docetaxel combination, and patients randomized in the experimental arm received concomitant bevacizumab. The primary endpoint was to describe ALDH1 (Aldehyde dehydrogenase 1) positive tumor cells rate before treatment and after the fourth cycle. Secondary objectives included safety, pathological complete response (pCR) rate, disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). Seventy-five patients were included. ALDH1+ cells rate increase was below the predefined 5% threshold in both arms for the 32 patients with two time points available. Grade 3 or 4 adverse events rates were similar in both arms. A non-significant increase in pCR was observed in the bevacizumab arm (42.6% vs. 18.2%, p = 0.06), but survival was not improved (OS: p = 0.89; DFS: p = 0.45; and RFS: p = 0.68). The increase of ALDH1+ tumor cells rate after bevacizumab-based chemotherapy was less than 5%. However, as similar results were observed with chemotherapy alone, bevacizumab impact on breast CSC cells cannot be confirmed. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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17 pages, 5140 KiB

Open AccessArticle

Cadherin 11 Inhibition Downregulates β-catenin, Deactivates the Canonical WNT Signalling Pathway and Suppresses the Cancer Stem Cell-Like Phenotype of Triple Negative Breast Cancer

by Pamungkas Bagus Satriyo, Oluwaseun Adebayo Bamodu, Jia-Hong Chen, Teguh Aryandono, Sofia Mubarika Haryana, Chi-Tai Yeh and Tsu-Yi Chao

J. Clin. Med. 2019, 8(2), 148; https://doi.org/10.3390/jcm8020148 - 27 Jan 2019

Cited by 51 | Viewed by 8815

Abstract

Background: Cancer stem cells (CSCs) promote tumor progression and distant metastasis in breast cancer. Cadherin 11 (CDH11) is overexpressed in invasive breast cancer cells and implicated in distant bone metastases in several cancers. The WNT signalling pathway regulates CSC activity. Growing evidence suggest that cadherins play critical roles in WNT signalling pathway. However, CDH11 role in canonical WNT signalling and CSCs in breast cancer is poorly understood. Methods: We investigated the functional association between CDH11 and WNT signalling pathway in triple negative breast cancer (TNBC), by analyzing their expression profile in the TCGA Breast Cancer (BRCA) cohort and immunohistochemical (IHC) staining of TNBC samples. Results: We observed a significant correlation between high CDH11 expression and poor prognosis in the basal and TNBC subtypes. Also, CDH11 expression positively correlated with β-catenin, wingless type MMTV integration site (WNT)2, and transcription factor (TCF)12 expression. IHC results showed CDH11 and β-catenin expression significantly correlated in TNBC patients (p < 0.05). We also showed that siRNA-mediated loss-of-CDH11 (siCDH11) function decreases β-catenin, Met, c-Myc, and matrix metalloproteinase (MMP)7 expression level in MDA-MB-231 and Hs578t. Interestingly, immunofluorescence staining showed that siCDH11 reduced β-catenin nuclear localization and attenuated TNBC cell migration, invasion and tumorsphere-formation. Of translational relevance, siCDH11 exhibited significant anticancer efficacy in murine tumor xenograft models, as demonstrated by reduced tumor-size, inhibited tumor growth and longer survival time. Conclusions: Our findings indicate that by modulating β-catenin, CDH11 regulates the canonical WNT signalling pathway. CDH11 inhibition suppresses the CSC-like phenotypes and tumor growth of TNBC cells and represents a novel therapeutic approach in TNBC treatment. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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Review

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24 pages, 4676 KiB

Open AccessReview

Different Shades of L1CAM in the Pathophysiology of Cancer Stem Cells

by Marco Giordano and Ugo Cavallaro

J. Clin. Med. 2020, 9(5), 1502; https://doi.org/10.3390/jcm9051502 - 16 May 2020

Cited by 36 | Viewed by 7326

Abstract

L1 cell adhesion molecule (L1CAM) is aberrantly expressed in several tumor types where it is causally linked to malignancy and therapy resistance, acting also as a poor prognosis factor. Accordingly, several approaches have been developed to interfere with L1CAM function or to deliver cytotoxic agents to L1CAM-expressing tumors. Metastatic dissemination, tumor relapse and drug resistance can be fueled by a subpopulation of neoplastic cells endowed with peculiar biological properties that include self-renewal, efficient DNA repair, drug efflux machineries, quiescence, and immune evasion. These cells, known as cancer stem cells (CSC) or tumor-initiating cells, represent, therefore, an ideal target for tumor eradication. However, the molecular and functional traits of CSC have been unveiled only to a limited extent. In this context, it appears that L1CAM is expressed in the CSC compartment of certain tumors, where it plays a causal role in stemness itself and/or in biological processes intimately associated with CSC (e.g., epithelial-mesenchymal transition (EMT) and chemoresistance). This review summarizes the role of L1CAM in cancer focusing on its functional contribution to CSC pathophysiology. We also discuss the clinical usefulness of therapeutic strategies aimed at targeting L1CAM in the context of anti-CSC treatments. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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10 pages, 1294 KiB

Open AccessReview

Comparison of the Genomic Profile of Cancer Stem Cells and Their Non-Stem Counterpart: The Case of Ovarian Cancer

by Elena Laura Mazzoldi, Anna Pastò, Giorgia Pilotto, Sonia Minuzzo, Ilaria Piga, Pietro Palumbo, Massimo Carella, Simona Frezzini, Maria Ornella Nicoletto, Alberto Amadori and Stefano Indraccolo

J. Clin. Med. 2020, 9(2), 368; https://doi.org/10.3390/jcm9020368 - 29 Jan 2020

Cited by 9 | Viewed by 3437

Abstract

The classical cancer stem cell (CSC) model places CSCs at the apex of a hierarchical scale, suggesting different genetic alterations in non-CSCs compared to CSCs, since an ill-defined number of cell generations and time intervals separate CSCs from the more differentiated cancer cells that form the bulk of the tumor. Another model, however, poses that CSCs should be considered a functional state of tumor cells, hence sharing the same genetic alterations. Here, we review the existing literature on the genetic landscape of CSCs in various tumor types and as a case study investigate the genomic complexity of DNA obtained from matched CSCs and non-CSCs from five ovarian cancer patients, using a genome-wide single-nucleotide polymorphism (SNP) microarray. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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22 pages, 2653 KiB

Open AccessReview

Wnt Signaling in Ovarian Cancer Stemness, EMT, and Therapy Resistance

by Miriam Teeuwssen and Riccardo Fodde

J. Clin. Med. 2019, 8(10), 1658; https://doi.org/10.3390/jcm8101658 - 11 Oct 2019

Cited by 165 | Viewed by 12555

Abstract

Ovarian cancers represent the deadliest among gynecologic malignancies and are characterized by a hierarchical structure with cancer stem cells (CSCs) endowed with self-renewal and the capacity to differentiate. The Wnt/β-catenin signaling pathway, known to regulate stemness in a broad spectrum of stem cell niches including the ovary, is thought to play an important role in ovarian cancer. Importantly, Wnt activity was shown to correlate with grade, epithelial to mesenchymal transition, chemotherapy resistance, and poor prognosis in ovarian cancer. This review will discuss the current knowledge of the role of Wnt signaling in ovarian cancer stemness, epithelial to mesenchymal transition (EMT), and therapy resistance. In addition, the alleged role of exosomes in the paracrine activation of Wnt signaling and pre-metastatic niche formation will be reviewed. Finally, novel potential treatment options based on Wnt inhibition will be highlighted. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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27 pages, 1487 KiB

Open AccessReview

Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors

by Maria Serena Roca, Elena Di Gennaro and Alfredo Budillon

J. Clin. Med. 2019, 8(7), 912; https://doi.org/10.3390/jcm8070912 - 26 Jun 2019

Cited by 38 | Viewed by 5246

Abstract

Resistance to therapy in patients with solid cancers represents a daunting challenge that must be addressed. Indeed, current strategies are still not effective in the majority of patients; which has resulted in the need for novel therapeutic approaches. Cancer stem cells (CSCs), a subset of tumor cells that possess self-renewal and multilineage differentiation potential, are known to be intrinsically resistant to anticancer treatments. In this review, we analyzed the implications for CSCs in drug resistance and described that multiple alterations in morphogenetic pathways (i.e., Hippo, Wnt, JAK/STAT, TGF-β, Notch, Hedgehog pathways) were suggested to be critical for CSC plasticity. By interrogating The Cancer Genome Atlas (TCGA) datasets, we first analyzed the prevalence of morphogenetic pathways alterations in solid tumors with associated outcomes. Then, by highlighting epigenetic relevance in CSC development and maintenance, we selected histone deacetylase inhibitors (HDACi) as potential agents of interest to target this subpopulation based on the pleiotropic effects exerted specifically on altered morphogenetic pathways. In detail, we highlighted the role of HDACi in solid cancers and, specifically, in the CSC subpopulation and we pointed out some mechanisms by which HDACi are able to overcome drug resistance and to modulate stemness. Although, further clinical and preclinical investigations should be conducted to disclose the unclear mechanisms by which HDACi modulate several signaling pathways in different tumors. To date, several lines of evidence support the testing of novel combinatorial therapeutic strategies based on the combination of drugs commonly used in clinical practice and HDACi to improve therapeutic efficacy in solid cancer patients. Full article

(This article belongs to the Special Issue New Aspects of Cancer Stem Cell Biology: Implications for Innovative Therapies)

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