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Biomedicines
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Recent Advances in Cancer Stem Cells
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Recent Advances in Cancer Stem Cells

A topical collection in Biomedicines (ISSN 2227-9059). This collection belongs to the section "Cell Biology and Pathology".

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Editor

Dr. Xiaoyan Jiang

E-Mail Website
Collection Editor
Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
Interests: basic and translational leukemia research; leukemic stem cell biology; drug resistance; gene regulation and proteome dynamics; oncolytic virotherapy and immunotherapy

Topical Collection Information

Dear Colleagues,

Cancer stem cells (CSCs) are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are shown to be involved in tumour initiation, poor prognosis and metastasis as well as therapy resistance. In this Topic Collection of Biomedicines, our aim is to provide hot information on topics like the mechanisms underpinning CSC biology contributing to tumour heterogeneity and cancer treatment. We invite research and review papers in the broad field of cancer stem cells, including, but not limited to: molecular mechanisms driving CSC plasticity; interaction with tumor microenvironment; immune evasion; cell signaling and therapy resistance related topics.

Dr. Xiaoyan Jiang
Collection Editor

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 collection 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. Biomedicines 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 2600 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.

Published Papers (3 papers)

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2023

Jump to: 2022

21 pages, 1570 KiB  
Review
Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment
by Ferenc Sipos and Györgyi Műzes
Biomedicines 2023, 11(1), 189; https://doi.org/10.3390/biomedicines11010189 - 11 Jan 2023
Cited by 14 | Viewed by 3462
Abstract
Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the [...] Read more.
Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the immune microenvironment remains unexplored. Although evasion of the immune system by CSCs has been extensively studied, new research demonstrates that CSCs can also control and even profit from the immune response. This review provides an overview of the reciprocal interplay between CSCs and tumor-infiltrating immune cells, collecting pertinent data about how CSCs stimulate leukocyte reprogramming, resulting in pro-tumor immune cells that promote metastasis, chemoresistance, tumorigenicity, and even a rise in the number of CSCs. Tumor-associated macrophages, neutrophils, Th17 and regulatory T cells, mesenchymal stem cells, and cancer-associated fibroblasts, as well as the signaling pathways involved in these pro-tumor activities, are among the immune cells studied. Although cytotoxic leukocytes have the potential to eliminate CSCs, immune evasion mechanisms in CSCs and their clinical implications are also known. We intended to compile experimental findings that provide direct evidence of interactions between CSCs and the immune system and CSCs and the inflammatory milieu. In addition, we aimed to summarize key concepts in order to comprehend the cross-talk between CSCs and the tumor microenvironment as a crucial process for the effective design of anti-CSC therapies. Full article
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Figure 1

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<p>CSCs have multiple ways of ensuring their own survival. In addition to affecting basic cellular functions, they can also alter the anti-tumor function of the immune system. The figure was partly created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 2
<p>There is an intense association between CSCs and the inflammatory TME. CSCs are able to use immune-competent cells to their own advantage. At the same time, inflammatory TME cells promote the survival of CSCs. Green arrows indicate a stimulatory effect, while the red arrow indicates inhibition. The figure was partly created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">

2022

Jump to: 2023

17 pages, 3316 KiB  
Article
Polymer Thin Film Promotes Tumor Spheroid Formation via JAK2-STAT3 Signaling Primed by Fibronectin-Integrin α5 and Sustained by LMO2-LDB1 Complex
by Sunyoung Seo, Nayoung Hong, Junhyuk Song, Dohyeon Kim, Yoonjung Choi, Daeyoup Lee, Sangyong Jon and Hyunggee Kim
Biomedicines 2022, 10(11), 2684; https://doi.org/10.3390/biomedicines10112684 - 24 Oct 2022
Cited by 1 | Viewed by 2206
Abstract
Cancer stem-like cells (CSCs) are considered promising targets for anti-cancer therapy owing to their role in tumor progression. Extensive research is, therefore, being carried out on CSCs to identify potential targets for anti-cancer therapy. However, this requires the availability of patient-derived CSCs ex [...] Read more.
Cancer stem-like cells (CSCs) are considered promising targets for anti-cancer therapy owing to their role in tumor progression. Extensive research is, therefore, being carried out on CSCs to identify potential targets for anti-cancer therapy. However, this requires the availability of patient-derived CSCs ex vivo, which remains restricted due to the low availability and diversity of CSCs. To address this limitation, a functional polymer thin-film (PTF) platform was invented to induce the transformation of cancer cells into tumorigenic spheroids. In this study, we demonstrated the functionality of a new PTF, polymer X, using a streamlined production process. Polymer X induced the formation of tumor spheroids with properties of CSCs, as revealed through the upregulated expression of CSC-related genes. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in the cancer cells cultured on polymer X was upregulated by the fibronectin-integrin α5-Janus kinase 2 (JAK2) axis and maintained by the cytosolic LMO2/LBD1 complex. In addition, STAT3 signaling was critical in spheroid formation on polymer X. Our PTF platform allows the efficient generation of tumor spheroids from cancer cells, thereby overcoming the existing limitations of cancer research. Full article
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<p>Acquisition of sphere formation ability and stemness signaling in the SKOV3 cells grown under polymer X culture condition. (<b>A</b>) Schematic illustration indicating the formation of tumor spheroid on polymer X. (<b>B</b>) Morphologies of SKOV3 cancer cells when cultured on TCP or polymer X for 8 days (d). Scale bar, 40 μm. (<b>C</b>) The mRNA levels of each indicated gene compared between cells cultured on TCP versus polymer X, as determined by real-time PCR. Data are expressed as mean ± SEM. Two-tailed Student’s <span class="html-italic">t</span>-test was used to analyze the statistical significance between each group (<span class="html-italic">n</span> = 3 for each group). b: <span class="html-italic">p</span> &lt; 0.01; c: <span class="html-italic">p</span> &lt; 0.001. (<b>D</b>) A schematic diagram showing GFP-negative population in cells cultured on polymer X and sorted by establishing a reporter system. (<b>E</b>) Image obtained by culturing each GFP-negative cell line transduced with each reporter system vector as indicated on polymer X for 8 days using IncuCyte system. Scale bar, 200 μm. (<b>F</b>) Gene set enrichment analysis (GSEA) displayed JAK-STAT3 signaling signature enrichment in SKOV3 cancer cells cultured on polymer X. (<b>G</b>) Cell lysates from SKOV3 cancer cells cultured on TCP or polymer X by date were immunoblotted with antibodies specific to pY705-STAT3 (p-STAT3), total STAT3, and α-tubulin. (<b>H</b>) The mRNA levels of the STAT3 target genes compared between cells cultured on TCP versus polymer X, as determined by real-time PCR. Data are expressed as mean ± SEM. Two-tailed Student’s <span class="html-italic">t</span>-test was used to analyze the statistical significance between each group (<span class="html-italic">n</span> = 3 for each group). c: <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 2
<p>Initial activation of STAT3 signaling was induced by fibronectin-JAK2 axis. (<b>A</b>) Functional network analysis of Gene Ontology (GO). Significantly enriched GO terms were visualized using the Cytoscape software add-on ClueGO plugin. The Benjamini–Hochberg false discovery rate was used to analyze statistical significance. Each node represents a significantly enriched GO term. (<b>B</b>) Image obtained by SKOV3 cancer cells cultured on polymer X or ULA for 8 days, and representative image displaying IF representing fibronectin expression in 8 days of SKOV3-derived tumor spheroids cultured on polymer X or ULA. Scale bar, 100 μm. (<b>C</b>) Cell lysates from SKOV3 cancer cells cultured on polymer X by date were immunoblotted with antibodies specific to FN1, integrin ɑ5, JAK1, JAK2, GP130, p-STAT3, total STAT3, and α-tubulin. (<b>D</b>) Cell lysates from SKOV3 cancer cells transfected with either non-target siRNA or si<span class="html-italic">FN1</span> cultured on polymer X on days 4 and 8 were immunoblotted with antibodies specific to FN1, integrin ɑ5, JAK1, JAK2, GP130, p-STAT3, total STAT3, and α-tubulin. (<b>E</b>) Image obtained by culturing STAT3 GFP-negative cell line transfected with either non-target siRNA or si<span class="html-italic">FN1</span>, cultured on polymer X for 8 days using IncuCyte system. Scale bar, 200 μm. (<b>F</b>) Cell lysates from SKOV3 cancer cells transfected with either non-target siRNA or si<span class="html-italic">JAK2</span>, cultured on polymer X on days 4 and 8, were immunoblotted with antibodies specific to JAK1, JAK2, GP130, p-STAT3, total STAT3, and α-tubulin. (<b>G</b>) Cell lysates from SKOV3 cancer cells transfected with either non-target siRNA or si<span class="html-italic">ITGA5</span>, cultured on TCP or polymer X on days 4 and 8, were immunoblotted with antibodies specific to integrin ɑ5, JAK1, JAK2, GP130, p-STAT3, total STAT3, and α-tubulin.</p> Full article ">Figure 3
<p>Long-term activation of STAT3 signaling via LMO2-LDB1 complex. (<b>A</b>) Cell lysates from SKOV3 cancer cells cultured on polymer X by date were immunoblotted with antibodies specific to JAK1, JAK2, GP130, p-STAT3, total STAT3, LMO2, LDB1, and α-tubulin. (<b>B</b>) Cell lysates from SKOV3 cancer cells transfected with either non-target siRNA or si<span class="html-italic">LMO2</span>, cultured on TCP or polymer X on days 4 and 8, were immunoblotted with antibodies specific to JAK1, JAK2, GP130, p-STAT3, total STAT3, LMO2, LDB1, and α-tubulin. (<b>C</b>) Cell lysates from SKOV3 cancer cells transfected with either non-target siRNA or si<span class="html-italic">LDB1</span>, cultured on TCP or polymer X on days 4 and 8, were immunoblotted with antibodies specific to JAK1, JAK2, GP130, p-STAT3, total STAT3, LMO2, LDB1, and α-tubulin. (<b>D</b>) Image obtained by culturing STAT3 GFP-negative cell line transfected with either non-target siRNA or si<span class="html-italic">LMO2</span> andsi<span class="html-italic">LDB1</span>, cultured on polymer X for 8 days using IncuCyte system. Scale bar, 200 μm. The arrow means LMO2.</p> Full article ">Figure 4
<p>Polymer X induced-tumor spheroids acquired cancer stem-like properties via STAT3 signaling. (<b>A</b>) A heatmap showing the mRNA levels of stemness markers obtained by knocking down each gene as displayed and performing real-time PCR. (<b>B</b>) Cell lysates from SKOV3 cancer cells treated with the STAT3 inhibitors, AG490 and nifuroxazide (NFZ), cultured on TCP or polymer X were immunoblotted with antibodies specific to JAK1, JAK2, GP130, p-STAT3, total STAT3, and α-tubulin. (<b>C</b>) Cell lysates from SKOV3 cancer cells treated with the STAT3 inhibitor, S3I-201, cultured on TCP or polymer X were immunoblotted with antibodies specific to p-STAT3, total STAT3, LDB1, LMO2, and ɑ-tubulin. (<b>D</b>) Images of tumor spheroids cultured on polymer X while administering STAT3 inhibitors. Scale bar, 40 μm. (<b>E</b>) The mRNA levels of STAT3 target genes in SKOV3 cancer cells treated with S3I-201 or vehicle were determined by real-time PCR. Data are expressed as mean ± SEM. Two-tailed Student’s <span class="html-italic">t</span>-test was used to analyze the statistical significance between each group (<span class="html-italic">n</span> = 3 for each group). a: <span class="html-italic">p</span> &lt; 0.05; b: <span class="html-italic">p</span> &lt; 0.01.(<b>F</b>) The mRNA levels of each indicated gene in SKOV3 cancer cells treated with S3I-201 or vehicle were determined by real-time PCR. Data are expressed as mean ± SEM. Two-tailed Student’s <span class="html-italic">t</span>-test was used to analyze the statistical significance between each group (<span class="html-italic">n</span> = 3 for each group). a: <span class="html-italic">p</span> &lt; 0.05; b: <span class="html-italic">p</span> &lt; 0.01; and c: <span class="html-italic">p</span> &lt; 0.001. (<b>G</b>) Cell lysates from SKOV3 cancer cells cultured on TCP and polymer X, and those cultured on polymer X and transferred to the TCP on days 2 and 4 were immunoblotted with antibodies specific to JAK1, JAK2, GP130, p-STAT3, total STAT3, LMO2, LDB1, and α-tubulin. (<b>H</b>) mRNA levels of each indicated gene in SKOV3 cancer cells cultured on TCP and polymer X, and those cultured on polymer X and transferred to the TCP on days 2 and 4 were determined by real-time PCR. Data are expressed as mean ± SEM. Two-tailed Student’s <span class="html-italic">t</span>-test was used to analyze the statistical significance between each group (<span class="html-italic">n</span> = 3 for each group). a: <span class="html-italic">p</span> &lt; 0.05; b: <span class="html-italic">p</span> &lt; 0.01; and c: <span class="html-italic">p</span> &lt; 0.001. The arrow means LMO2.</p> Full article ">Figure 5
<p>General application of polymer X using various cancer cell lines. (<b>A</b>) Images of tumor spheroids cultured in each indicated cell line on TCP or polymer X for 8 days. Scale bar, 40 μm. (<b>B</b>) Cell lysates from A1207 and LN18 GBM cells cultured on TCP or polymer X for 8 days were immunoblotted with antibodies specific to GP130, p-STAT3, total STAT3, LMO2, LDB1, and α-tubulin. (<b>C</b>) Cell lysates from U87MG and LN229 GBM cells cultured on TCP or polymer X for 8 days were immunoblotted with antibodies specific to GP130, p-STAT3, total STAT3, LMO2, LDB1, and α-tubulin. (<b>D</b>) Cell lysates from T98G GBM cells and HeLa cells cultured on TCP or polymer X for 8 days were immunoblotted with antibodies specific to GP130, p-STAT3, total STAT3, LMO2, LDB1, and ɑ-tubulin. The arrow means LMO2.</p> Full article ">
29 pages, 1629 KiB  
Review
Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias
by Xingjian Zhai and Xiaoyan Jiang
Biomedicines 2022, 10(8), 1841; https://doi.org/10.3390/biomedicines10081841 - 30 Jul 2022
Cited by 5 | Viewed by 4021
Abstract
Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique [...] Read more.
Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs. Full article
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<p><b>Stromal cellular signaling facilitates leukemic stem cell (LSC) survival, quiescence, and drug resistance.</b> LSCs engage in bidirectional crosstalk with multiple BM cellular constituents. E-selectin expressed on the surface of endothelial cells interacts with CD44 on LSCs to drive LSC homing and retention in the protective BM microenvironment, sheltering LSCs from therapeutic insults. Furthermore, endothelial cells also release microRNA (miRNA)-containing extracellular vesicles to further enrich the quiescence phenotype of LSCs. Osteoblasts primarily release proinflammatory cytokines that lead to the transcription of genes implicated in LSC survival, self-renewal, and quiescence. Mesenchymal stromal cells are known to physically transfer mitochondria to LSCs via nanotubes to repair and replace damaged mitochondria with new ones inside LSCs, potentially helping LSCs evade apoptosis. Mesenchymal stromal cells can also activate pro-survival integrin-mediated signaling in LSCs, involving the PI3K/AKT pathway. Moreover, adipocytes assist in the rewiring of LSC metabolism, supplying free fatty acids to fuel oxidative phosphorylation, a known metabolic dependency of LSCs.</p> Full article ">Figure 2
<p><b>Multi-omics circuitry of AML and CML LSC-mediated drug resistance.</b> (<b>a</b>) Notable transcriptomic features of AML LSCs include dysregulated transcription factors, such as STAT3, the aberrant activation of which is associated with the transcription of core stemness genes; constitutive NFκB activation, which can be mediated by a self-sustaining, autocrine positive feedback loop with tumor necrosis factor-α (TNF-α); and aberrant c-Myc activity, which, along with sp1, enhances transcription of <span class="html-italic">survivin</span>, concertedly driving LSC survival, self-maintenance, and drug resistance. Epigenetically, m<sup>6</sup>A RNA modification by METTL14 is essential for LSC self-renewal and frequency in vivo. In regard to the proteomic and metabolomic landscapes of AML LSCs, AML LSCs tend to harbor high abundance of mitochondrial ribosomes, also known as mito-ribosomes, to facilitate translation of mitochondrial and oxidative phosphorylation (OXPHOS) machineries, to which fatty acid oxidation contributes a great deal. Interestingly, AML LSCs generally maintain modest to low levels of reactive oxygen species (ROS), in alignment with their generally quiescent state. (<b>b</b>) CML LSCs have also shown oncogenic aberrations to transcription factor activities, including JAK2/STAT5 signaling, which activates transcription of pro-survival genes and confers TKI resistance. Dysregulation of P53 signaling by c-Myc or Acidic Nuclear Phosphoprotein 32 Family Member B (ANP32B) fosters LSC survival and self-maintenance. Furthermore, the AHI-1-BCR-ABL-JAK2-DNM2 signaling network facilitates multiple features of CML LSC survival and drug resistance, such as activating STAT5 signaling, increasing ROS production, and promoting genome instability, all of which drive overall LSC proliferation and resistance to therapy. The abilities of CML LSCs to self-renew and to resist against TKI therapy can further be enhanced by epigenetic mechanisms such as increased global DNA methylation and dysregulated miRNA milieu (e.g., downregulation of miR-185 or increased level of miR-26). Particularly, downregulation of miR-185 increases its target PAK6 level, which leads to increased OXPHOS capacity and ROS production of CML LSCs. Aberrant kinase activation, such as ERK/MEK, may partially account for proteomic anomalies underlying LSC survival. Like AML LSCs, CML LSCs tend to rely on OXPHOS to maintain cellular bioenergetics. However, unlike AML LSCs, CML LSCs thrive under elevated ROS, as it triggers further genome instability and potentially gives rise to TKI-resistant BCR-ABL mutations such as T315I.</p> Full article ">
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