-
Nature Medicine Oct 2017The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers... (Review)
Review
The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response. Here we discuss new developments in the CSC field in relationship to changing insights into how normal stem cells maintain healthy tissues. Expectations in the field have become more realistic, and now, the first successes of therapies based on the CSC concept are emerging.
Topics: Adult Stem Cells; Animals; Cell Lineage; Cell Plasticity; Cell Self Renewal; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Neoplastic Stem Cells; Stem Cells; Tumor Microenvironment
PubMed: 28985214
DOI: 10.1038/nm.4409 -
Cells Mar 2021The main difficulty of radiotherapy is to destroy cancer cells without depletion of healthy tissue [...].
The main difficulty of radiotherapy is to destroy cancer cells without depletion of healthy tissue [...].
Topics: Adult Stem Cells; Cell- and Tissue-Based Therapy; Homeostasis; Humans; Neoplastic Stem Cells; Organoids; Radiation; Stem Cells
PubMed: 33808269
DOI: 10.3390/cells10040760 -
Stem Cell Reviews and Reports Jun 2018MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental... (Review)
Review
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apoptosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function. Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs could be regulated to influence cell cycle progression in stem cells as a potential clinical application.
Topics: Adult Stem Cells; Animals; Cell Cycle; Humans; MicroRNAs; Neoplastic Stem Cells; Stem Cells
PubMed: 29541978
DOI: 10.1007/s12015-018-9808-y -
Cell Reports Aug 2022Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis.... (Review)
Review
Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis. CTCs face critical challenges for their survival in circulation, such as anoikis, shearing forces, and immune surveillance. Thus, understanding the mechanisms and interactions of CTCs within the blood microenvironment is crucial for better understanding of metastatic progression and the development of novel treatment strategies. CTCs interact with different hematopoietic cells, such as platelets, red blood cells, neutrophils, macrophages, natural killer (NK) cells, lymphocytes, endothelial cells, and cancer-associated fibroblasts, which can affect CTC survival in blood. This interaction may take place either via direct cell-cell contact or through secreted molecules. Here, we review interactions of CTCs with blood cells and discuss the potential clinical relevance of these interactions as biomarkers or as targets for anti-metastatic therapies.
Topics: Biology; Biomarkers, Tumor; Blood Cells; Cell Count; Endothelial Cells; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Tumor Microenvironment
PubMed: 36044866
DOI: 10.1016/j.celrep.2022.111298 -
Molecular Cell May 2017Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to... (Review)
Review
Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, which would be particularly detrimental to the whole organism. Inducible pluripotent stem cells also display a robust DNA damage response, but the stability of their genome is often conditioned by the mutational history of the cell population of origin, which constitutes an obstacle to clinical applications. Cancer stem cells are particularly tolerant to DNA damage and fail to undergo senescence or regulated cell death upon accumulation of genetic lesions. Such a resistance contributes to the genetic drift of evolving tumors as well as to their limited sensitivity to chemo- and radiotherapy. Here, we discuss the pathophysiological and therapeutic implications of the molecular pathways through which stem cells cope with DNA damage.
Topics: Adult Stem Cells; Animals; DNA Damage; DNA Repair; Embryonic Stem Cells; Genetic Drift; Genomic Instability; Humans; Mutation; Neoplasms; Neoplastic Stem Cells; Pluripotent Stem Cells; Radiation Tolerance
PubMed: 28475867
DOI: 10.1016/j.molcel.2017.04.006 -
Neoplasia (New York, N.Y.) Jan 2015Three-dimensional (3D) in vitro models have been used in cancer research as an intermediate model between in vitro cancer cell line cultures and in vivo tumor. Spherical... (Review)
Review
Three-dimensional (3D) in vitro models have been used in cancer research as an intermediate model between in vitro cancer cell line cultures and in vivo tumor. Spherical cancer models represent major 3D in vitro models that have been described over the past 4 decades. These models have gained popularity in cancer stem cell research using tumorospheres. Thus, it is crucial to define and clarify the different spherical cancer models thus far described. Here, we focus on in vitro multicellular spheres used in cancer research. All these spherelike structures are characterized by their well-rounded shape, the presence of cancer cells, and their capacity to be maintained as free-floating cultures. We propose a rational classification of the four most commonly used spherical cancer models in cancer research based on culture methods for obtaining them and on subsequent differences in sphere biology: the multicellular tumor spheroid model, first described in the early 70s and obtained by culture of cancer cell lines under nonadherent conditions; tumorospheres, a model of cancer stem cell expansion established in a serum-free medium supplemented with growth factors; tissue-derived tumor spheres and organotypic multicellular spheroids, obtained by tumor tissue mechanical dissociation and cutting. In addition, we describe their applications to and interest in cancer research; in particular, we describe their contribution to chemoresistance, radioresistance, tumorigenicity, and invasion and migration studies. Although these models share a common 3D conformation, each displays its own intrinsic properties. Therefore, the most relevant spherical cancer model must be carefully selected, as a function of the study aim and cancer type.
Topics: Animals; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; In Vitro Techniques; Neoplasms; Neoplastic Stem Cells; Radiation Tolerance; Spheroids, Cellular; Tissue Culture Techniques; Tumor Cells, Cultured
PubMed: 25622895
DOI: 10.1016/j.neo.2014.12.004 -
Cancer Science Mar 2017Recently, many types of in vitro 3-D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3-D culture methods aim to... (Review)
Review
Recently, many types of in vitro 3-D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3-D culture methods aim to preserve the biological characteristics of original tumors better than conventional 2-D monolayer cultures, and include tumor-derived organoids, tumor-derived spheroids, organotypic multicellular spheroids, and multicellular tumor spheroids. The 3-D culture methods differ in terms of cancer cell sources, protocols for cell handling, and the required time intervals. Tumor-derived spheroids are unique because they are purposed for the enrichment of cancer stem cells (CSCs) or cells with stem cell-related characteristics. These spheroids are grown as floating spheres and have been used as surrogate systems to evaluate the CSC-related characteristics of solid tumors in vitro. Because eradication of CSCs is likely to be of clinical importance due to their association with the malignant nature of cancer cells, such as tumorigenicity or chemoresistance, the investigation of tumor-derived spheroids may provide invaluable clues to fight against cancer. Spheroid cultures have been established from cancers including glioma, breast, colon, ovary, and prostate cancers, and their biological and biochemical characteristics have been investigated by many research groups. In addition to the investigation of CSCs, tumor-derived spheroids may prove to be instrumental for a high-throughput screening platform or for the cultivation of CSC-related tumor cells found in the circulation or body fluids.
Topics: Cell Culture Techniques; Humans; Neoplasms; Neoplastic Stem Cells; Spheroids, Cellular; Tumor Cells, Cultured
PubMed: 28064442
DOI: 10.1111/cas.13155 -
The Biochemical Journal Jan 2021Glioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSCs). Also, tumor...
Glioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSCs). Also, tumor networking and intercellular communication play a major role in driving GBM therapy-resistance. Tunneling Nanotubes (TNTs), thin membranous open-ended channels connecting distant cells, have been observed in several types of cancer, where they emerge to drive a more malignant phenotype. Here, we investigated whether GBM cells are capable to intercommunicate by TNTs. Two GBM stem-like cells (GSLCs) were obtained from the external and infiltrative zone of one GBM from one patient. We show, for the first time, that both GSLCs, grown in classical 2D culture and in 3D-tumor organoids, formed functional TNTs which allowed mitochondria transfer. In the organoid model, recapitulative of several tumor's features, we observed the formation of a network between cells constituted of both Tumor Microtubes (TMs), previously observed in vivo, and TNTs. In addition, the two GSLCs exhibited different responses to irradiation in terms of TNT induction and mitochondria transfer, although the correlation with the disease progression and therapy-resistance needs to be further addressed. Thus, TNT-based communication is active in different GSLCs derived from the external tumoral areas associated to GBM relapse, and we propose that they participate together with TMs in tumor networking.
Topics: Brain Neoplasms; Cell Communication; Cell Line, Tumor; Cell Surface Extensions; Cells, Cultured; Disease Progression; GAP-43 Protein; Glioblastoma; Humans; Mitochondria; Neoplastic Stem Cells; Organoids; Radiation; Recurrence; Time-Lapse Imaging
PubMed: 33245115
DOI: 10.1042/BCJ20200710 -
Cell Cycle (Georgetown, Tex.) 2018Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer.... (Review)
Review
Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer. Mitochondria are increasingly recognized key drivers in the origin and development of CSC functional traits. We here propose the new term "mitostemness" to designate the mitochondria-dependent signaling functions that, evolutionary rooted in the bacterial origin of mitochondria, regulate the maintenance of CSC self-renewal and resistance to differentiation. Mitostemness traits, namely mitonuclear communication, mitoproteome components, and mitochondrial fission/fusion dynamics, can be therapeutically exploited to target the CSC state. We briefly review the pre-clinical evidence of action of investigational compounds on mitostemness traits and discuss ongoing strategies to accelerate the clinical translation of new mitostemness drugs. The recognition that the bacterial origin of present-day mitochondria can drive decision-making signaling phenomena may open up a new therapeutic dimension against life-threatening CSCs. New therapeutics aimed to target mitochondria not only as biochemical but also as biophysical and morpho-physiological hallmarks of CSC might certainly guide improvements to cancer treatment.
Topics: Antineoplastic Agents; Bacteria; Cell Nucleus; Humans; Mitochondria; Mitochondrial Dynamics; Neoplastic Stem Cells
PubMed: 29886796
DOI: 10.1080/15384101.2018.1467679 -
Cancer Cell Nov 2011Interactions of cancer cells with the primary tumor microenvironment are important determinants of cancer progression toward metastasis but it is unknown whether...
Interactions of cancer cells with the primary tumor microenvironment are important determinants of cancer progression toward metastasis but it is unknown whether additional prometastatic signals are provided during the intravascular transit to the site of metastasis. Here, we show that platelet-tumor cell interactions are sufficient to prime tumor cells for subsequent metastasis. Platelet-derived TGFβ and direct platelet-tumor cell contacts synergistically activate the TGFβ/Smad and NF-κB pathways in cancer cells, resulting in their transition to an invasive mesenchymal-like phenotype and enhanced metastasis in vivo. Inhibition of NF-κB signaling in cancer cells or ablation of TGFβ1 expression solely in platelets protects against lung metastasis in vivo. Thus, cancer cells rely on platelet-derived signals outside of the primary tumor for efficient metastasis.
Topics: Animals; Blood Platelets; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Lung Neoplasms; Mice; Mice, Inbred C57BL; Molecular Sequence Data; NF-kappa B; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Cells, Circulating; Signal Transduction; Transforming Growth Factor beta1
PubMed: 22094253
DOI: 10.1016/j.ccr.2011.09.009