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Cancer Stem Cells in Basic Science and in Translational Oncology

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 December 2021) | Viewed by 17263

Special Issue Editors

Department of Pharmacology and Toxicology, Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA
Interests: cancer; stem cells; cancer stem cells; gene therapy
Special Issues, Collections and Topics in MDPI journals
Center of Investigation in Environment, Genetics and Oncobiology, University of Coimbra, Coimbra, Portugal
Interests: cancer stem cells; drug resistance; self-renewal pathways; metastasis; theranostics; exosomes; solid tumors
Special Issues, Collections and Topics in MDPI journals
Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR) - Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Interests: cancer stem cells; bone sarcomas; solid tumors; cancer chemoresistance; scientific communication
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer stem cells (CSCs) are a small subpopulation of cells within malignant tumors gifted with self-renewal, differentiation, and tumorigenicity capabilities when transplanted in animals. Their ability to generate differentiated cells is thought to contribute to tumor heterogeneity. CSCs are intrinsically therapy-resistant and therefore are considered to be at the origin of recurrence in cancer patients following chemoradiation therapy.  

This issue will focus on recent advances in the discovery of targeted therapies, translation of diagnostic assays, therapeutic interventions aimed at reducing the CSCs load in cancer patients, precision medicine, and the role of CSCs in chemoradiation resistance and cancer progression, with the aim to highlight emerging therapeutic strategies against these highly malignant cells. Pure clinical studies will not be suitable, but clinical submissions with biomolecular studies having the major goal to translate into the clinic findings related to the role of CSCs in the progression of cancer are welcomed.

Prof. Dr. Pier Paolo Claudio
Dr. Célia Maria Freitas Gomes
Dr. Sara R. Martins-Neves
Guest Editors

Manuscript Submission Information

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Keywords

  • Cancer stem cells
  • Precision medicine
  • Translational oncology
  • Chemoradiation resistance
  • Metastasis
  • Tumor microenvironment

Published Papers (6 papers)

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Research

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17 pages, 3220 KiB  
Article
Dickkopf-1 Promotes Angiogenesis and is a Biomarker for Hepatic Stem Cell-like Hepatocellular Carcinoma
by Tsuyoshi Suda, Taro Yamashita, Hajime Sunagozaka, Hikari Okada, Kouki Nio, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda and Shuichi Kaneko
Int. J. Mol. Sci. 2022, 23(5), 2801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052801 - 03 Mar 2022
Cited by 14 | Viewed by 2202
Abstract
Cancer stemness evinces interest owing to the resulting malignancy and poor prognosis. We previously demonstrated that hepatic stem cell-like hepatocellular carcinoma (HpSC-HCC) is associated with high vascular invasion and poor prognosis. Dickkopf-1 (DKK-1), a Wnt signaling regulator, is highly expressed in HpSC-HCC. Here, [...] Read more.
Cancer stemness evinces interest owing to the resulting malignancy and poor prognosis. We previously demonstrated that hepatic stem cell-like hepatocellular carcinoma (HpSC-HCC) is associated with high vascular invasion and poor prognosis. Dickkopf-1 (DKK-1), a Wnt signaling regulator, is highly expressed in HpSC-HCC. Here, we assessed the diagnostic and prognostic potential of serum DKK-1. Its levels were significantly higher in 391 patients with HCC compared with 205 patients with chronic liver disease. Receiver operating characteristic curve analysis revealed the optimal cutoff value of DKK-1 to diagnose HCC and predict the 3-year survival as 262.2 and 365.9 pg/mL, respectively. HCC patients with high-serum DKK-1 levels showed poor prognosis. We evaluated the effects of anti-DKK-1 antibody treatment on tumor growth in vivo and of recombinant DKK-1 on cell proliferation, invasion, and angiogenesis in vitro. DKK-1 knockdown decreased cancer cell proliferation, migration, and invasion. DKK-1 supplementation promoted angiogenesis in vitro; this effect was abolished by an anti-DKK-1 antibody. Co-injection of the anti-DKK-1 antibody with Huh7 cells inhibited their growth in NOD/SCID mice. Thus, DKK-1 promotes proliferation, migration, and invasion of HCC cells and activates angiogenesis in vascular endothelial cells. DKK-1 is a prognostic biomarker for HCC and a functional molecule for targeted therapy. Full article
(This article belongs to the Special Issue Cancer Stem Cells in Basic Science and in Translational Oncology)
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20 pages, 5244 KiB  
Article
Keratin Profiling by Single-Cell RNA-Sequencing Identifies Human Prostate Stem Cell Lineage Hierarchy and Cancer Stem-Like Cells
by Wen-Yang Hu, Dan-Ping Hu, Lishi Xie, Larisa Nonn, Ranli Lu, Michael Abern, Toshihiro Shioda and Gail S. Prins
Int. J. Mol. Sci. 2021, 22(15), 8109; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158109 - 28 Jul 2021
Cited by 6 | Viewed by 3505
Abstract
Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we [...] Read more.
Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we characterized the epithelial cell lineage hierarchy in prostaspheres using single-cell RNA-seq analysis. Keratin profiling revealed three clusters of label-retaining prostate stem cells; cluster I represents quiescent stem cells (PSCA, CD36, SPINK1, and KRT13/23/80/78/4 enriched), while clusters II and III represent active stem and bipotent progenitor cells (KRT16/17/6 enriched). Gene set enrichment analysis revealed enrichment of stem and cancer-related pathways in cluster I. In non-label-retaining daughter progenitor cells, three clusters were identified; cluster IV represents basal progenitors (KRT5/14/6/16 enriched), while clusters V and VI represent early and late-stage luminal progenitors, respectively (KRT8/18/10 enriched). Furthermore, MetaCore analysis showed enrichment of the “cytoskeleton remodeling–keratin filaments” pathway in cancer stem-like cells from human prostate cancer specimens. Along with common keratins (KRT13/23/80/78/4) in normal stem cells, unique keratins (KRT10/19/6C/16) were enriched in cancer stem-like cells. Clarification of these keratin profiles in human prostate stem cell lineage hierarchy and cancer stem-like cells can facilitate the identification and therapeutic targeting of prostate cancer stem-like cells. Full article
(This article belongs to the Special Issue Cancer Stem Cells in Basic Science and in Translational Oncology)
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12 pages, 4437 KiB  
Article
S1P Lyase Regulates Intestinal Stem Cell Quiescence via Ki-67 and FOXO3
by Anja Schwiebs, Farha Faqar-Uz-Zaman, Martina Herrero San Juan and Heinfried H. Radeke
Int. J. Mol. Sci. 2021, 22(11), 5682; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115682 - 26 May 2021
Cited by 3 | Viewed by 2757
Abstract
Background: Reduction of the Sphingosine-1-phosphate (S1P) degrading enzyme S1P lyase 1 (SGPL1) initiates colorectal cancer progression with parallel loss of colon function in mice. We aimed to investigate the effect of SGPL1 knockout on the stem cell niche in these mice. Methods: We [...] Read more.
Background: Reduction of the Sphingosine-1-phosphate (S1P) degrading enzyme S1P lyase 1 (SGPL1) initiates colorectal cancer progression with parallel loss of colon function in mice. We aimed to investigate the effect of SGPL1 knockout on the stem cell niche in these mice. Methods: We performed immunohistochemical and multi-fluorescence imaging on tissue sections of wildtype and SGPL1 knockout colons under disease conditions. Furthermore, we generated SGPL1 knockout DLD-1 cells (SGPL1−/−M.Ex1) using CRISPR/Cas9 and characterized cell cycle and AKT signaling pathway via Western blot, immunofluorescence, and FACS analysis. Results: SGPL1 knockout mice were absent of anti-Ki-67 staining in the stem cell niche under disease conditions. This was accompanied by an increase of the negative cell cycle regulator FOXO3 and attenuation of CDK2 activity. SGPL1−/−M.Ex1 cells show a similar FOXO3 increase but no arrest of proliferation, although we found a suppression of the PDK1/AKT signaling pathway, a prolonged G1-phase, and reduced stem cell markers. Conclusions: While already established colon cancer cells find escape mechanisms from cell cycle arrest, in vivo SGPL1 knockout in the colon stem cell niche during progression of colorectal cancer can contribute to cell cycle quiescence. Thus, we propose a new function of the S1P lyase 1 in stemness. Full article
(This article belongs to the Special Issue Cancer Stem Cells in Basic Science and in Translational Oncology)
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20 pages, 4902 KiB  
Article
The Stemness-High Human Colorectal Cancer Cells Promote Angiogenesis by Producing Higher Amounts of Angiogenic Cytokines via Activation of the Egfr/Akt/Nf-κB Pathway
by Shin-Yi Chung, Ta-Chung Chao and Yeu Su
Int. J. Mol. Sci. 2021, 22(3), 1355; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031355 - 29 Jan 2021
Cited by 11 | Viewed by 2235
Abstract
Purpose: Cancer stem cells (CSCs) are responsible for cancer metastasis by stimulating tumor angiogenesis via various mechanisms. To elucidate the potential of the stemness-high human colorectal cancer (CRC) cells (i.e., CRCSCs) in activating angiogenesis, effects of the GATA6-overexpressing HCT-116 and HT-29 human CRC [...] Read more.
Purpose: Cancer stem cells (CSCs) are responsible for cancer metastasis by stimulating tumor angiogenesis via various mechanisms. To elucidate the potential of the stemness-high human colorectal cancer (CRC) cells (i.e., CRCSCs) in activating angiogenesis, effects of the GATA6-overexpressing HCT-116 and HT-29 human CRC clones established previously by us in promoting the angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined. Methods: Angiogenesis-promoting effects (i.e., migration, invasion, DNA synthesis, and tube formation) in HUVECs of the conditioned media (CM) from various human CRC clones were analyzed. MMP activities were assessed using a zymography assay. Western blotting and selective inhibitors were used to dissect the signaling pathway involved. IHC was used to examine the vascular density in tumor xenografts. Results: We found that the conditioned media (CM) collected from the GATA6-overexpressing clones enhanced angiogenesis of HUVECs more effectively which might be attributed partly to a higher MMP-9 production by HUVECs. Subsequently, elevated levels of IL-8 and VEGF-A were detected in the CM whose tube formation-enhancing activities were abolished by the co-treatment with either a VEGFR2 inhibitor or an IL-8 neutralizing antibody. Interestingly, increased production of these cytokines in the GATA6-overexpressing clones was due to an EGFR/AKT-mediated activation of NF-κB. Furthermore, not only were the levels of CD31 and endomucin but also the blood vessel density was much higher in the xenograft tumors grown from these clones. Conclusion: Our findings demonstrate that human CRCSCs promote a stronger angiogenesis by producing higher amounts of angiogenic factors through activation of the EGFR/AKT/NF-κB pathway. Full article
(This article belongs to the Special Issue Cancer Stem Cells in Basic Science and in Translational Oncology)
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Review

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17 pages, 343 KiB  
Review
Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment
by Agnieszka Kaczmarska, Patrycja Śliwa, Joanna Zawitkowska and Monika Lejman
Int. J. Mol. Sci. 2021, 22(12), 6411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126411 - 15 Jun 2021
Cited by 6 | Viewed by 2759
Abstract
Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in [...] Read more.
Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in their first remission (CR1). Over the last few years, the treatment of childhood ALL has significantly improved due to standardized research protocols. Hematopoietic stem cell transplantation (HSCT) has been the gold standard therapy in ALL Ph+ patients, but recently first-generation tyrosine kinase inhibitor (TKI)-imatinib became a major milestone in increasing overall survival. Genomic analyses give the opportunity for the investigation of new fusions or mutations, which can be used to establish effective targeted therapies. Alterations of the IKZF1 gene are present in a large proportion of pediatric and adult ALL Ph+ cases. IKZF1 deletions are present in ~15% of patients without BCR-ABL1 rearrangements. In BCR-ABL1-negative cases, IKZF1 deletions have been shown to have an independent prognostic impact, carrying a three-fold increased risk of treatment failure. The prognostic significance of IKZF1 gene aberrations in pediatric ALL Ph+ is still under investigation. More research should focus on targeted therapies and immunotherapy, which is not associated with serious toxicity in the same way as classic chemotherapy, and on the improvement of patient outcomes. In this review, we provide a molecular analysis of childhood ALL with t(9;22)(q34;q11.2), including the Ph-like subtype, and of treatment strategies. Full article
(This article belongs to the Special Issue Cancer Stem Cells in Basic Science and in Translational Oncology)
15 pages, 1119 KiB  
Review
The Role of lncRNAs in the Stem Phenotype of Pancreatic Ductal Adenocarcinoma
by Jorge Melendez-Zajgla and Vilma Maldonado
Int. J. Mol. Sci. 2021, 22(12), 6374; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126374 - 15 Jun 2021
Cited by 12 | Viewed by 2533
Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem [...] Read more.
Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem cells have been isolated and characterized from these tumors, showing their dependance on general and tissue-specific stem transcription factors and signaling pathways. Nevertheless, little is known about their tissue microenvironment and cell non-autonomous regulators, such as long-non-coding RNAs. (lncRNAs). In this review, we summarize the current knowledge about the positive and negative effects of lncRNAs in the stemness phenotype of pancreatic ductal adenocarcinoma cancer (PDAC). Full article
(This article belongs to the Special Issue Cancer Stem Cells in Basic Science and in Translational Oncology)
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