Stem cells in genetically-engineered mouse models of prostate cancer

The cancer stem cell model proposes that tumors have a hierarchical organization in which tumorigenic cells give rise to non-tumorigenic cells, with only a subset of stem-like cells able to propagate the tumor. In the case of prostate cancer, recent analyses of genetically engineered mouse (GEM) models have provided evidence supporting the existence of cancer stem cells in vivo. These studies suggest that cancer stem cells capable of tumor propagation exist at various stages of tumor progression from prostatic intraepithelial neoplasia (PIN) to advanced metastatic and castration-resistant disease. However, studies of stem cells in prostate cancer have been limited by available approaches for evaluating their functional properties in cell culture and transplantation assays. Given the role of the tumor microenvironment and the putative cancer stem cell niche, future studies using GEM models to analyze cancer stem cells in their native tissue microenvironment are likely to be highly informative.

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Invincible, but Not Invisible: Imaging Approaches Toward In Vivo Detection of Cancer Stem Cells

Journal of Clinical Oncology ◽

10.1200/jco.2008.16.9573 ◽

2008 ◽

Vol 26 (17) ◽

pp. 2901-2910 ◽

Cited By ~ 45

Author(s):

Lori S. Hart ◽

Wafik S. El-Deiry

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Natural Environment ◽

Cell Model ◽

Advanced Imaging ◽

Stem Cell Model ◽

Cancer Stem Cell Model

With evidence emerging in support of a cancer stem-cell model of carcinogenesis, it is of paramount importance to identify and image these elusive cells in their natural environment. The cancer stem-cell hypothesis has the potential to explain unresolved questions of tumorigenesis, tumor heterogeneity, chemotherapeutic and radiation resistance, and even the metastatic phenotype. Intravital imaging of cancer stem cells could be of great value for determining prognosis, as well as monitoring therapeutic efficacy and influencing therapeutic protocols. Cancer stem cells represent a rare population of cells, as low as 0.1% of cells within a human tumor, and the phenotype of isolated cancer stem cells is easily altered when placed under in vitro conditions. This represents a challenge in studying cancer stem cells without manipulation or extraction from their natural environment. Advanced imaging techniques allow for the in vivo observation of physiological events at cellular resolution. Cancer stem-cell studies must take advantage of such technology to promote a better understanding of the cancer stem-cell model in relation to tumor growth and metastasis, as well as to potentially improve on the principles by which cancers are treated. This review examines the opportunities for in vivo imaging of putative cancer stem cells with regard to currently accepted cancer stem-cell characteristics and advanced imaging technologies.

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Molecular markers of cancer stem cells verified in vivo

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20166203228 ◽

2016 ◽

Vol 62 (3) ◽

pp. 228-238 ◽

Cited By ~ 7

Author(s):

Y.S. Kim ◽

A.M. Kaidina ◽

J.H. Chiang ◽

K.N. Yarygin ◽

A.Yu. Lupatov

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Molecular Markers ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Stem Cell Markers ◽

Cancer Stem Cell Markers ◽

Immunodeficient Mice ◽

Molecular Features

This systematic review aims to analyze molecular markers of cancer stem cells. Only studies that confirmed tumor-initiating capacity of this population by in vivo assay in immunodeficient mice were included. Final sample of papers that fully correspond with initial aim consists of 97 original studies. The results of their analysis reveal that markers commonly used for cancer stem cells deriving were as follows: CD133, СD44, ALDH, CD34, CD24 and EpCAM. The review also contains description of molecular features of some cancer stem cell markers, modern approaches to cancer treatment by targeting this population and brief assessment of cancer stem cell theory development.

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Effect of CD44 knockdown on the biological characteristics of breast cancer stem cells

10.21203/rs.3.rs-26900/v1 ◽

2020 ◽

Author(s):

Zi Lei ◽

Yang-Li Hu ◽

Qiang Feng ◽

Li Wang ◽

Xin-Yan Pan ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Biological Characteristics ◽

Breast Cancer Stem Cells ◽

Transcript Variants

Abstract Background: CD44 is an important surface marker of breast cancer stem cells (BCSCs), but it is unclear whether it is involved in the stemness of BCSCs. This has limited the development of new therapeutic strategies for breast cancer. Previous studies have shown that many CD44 variants generated through alternative splicing are involved in the development of breast cancer, but their exact role in BCSCs remains unclear. Therefore, we analyzed the CD44 transcript variants in BCSCs derived from the MDA-MB-435 cell line, and aimed to investigate whether CD44s knockdown could affect the biological characteristics of BCSCs.Methods: CD44+/CD24- cells were isolated among the MDA-MB-435 cells by flow cytometry, and the CD44 transcript variants were detected by RT-PCR in CD44+/CD24- cells. Due to the high expression of CD44 standard splice isoform (CD44s) in CD44+/CD24- cells, CD44s knockdown was generated using small hairpin RNA (shRNA). The effects of CD44s knockdown on the biological characteristics of BCSCs was detected using cell proliferation assay, colony formation assay, cell cycle and apoptosis assay, tumor sphere formation assay, would-healing assay, and Matrigel invasion assay. Tumorigenesis of the CD44+/CD24- cells with CD44s knockdown was investigated in vivo with NOD/SCID mice. The expression of cancer stem cell stemness-related genes, such as Bcl-2, CCNE2, EGFR, MMP7, Muc1, and Myc was also detected by qPCR.Results: Our results revealed that the mRNA expression of CD44 transcript variants was heterogeneous, and CD44s is highly expressed in BCSCs. CD44s depletion inhibited the proliferation, made cell cycle stay in G0/G1 phase, promoted the apoptosis and necrosis of BCSCs, inhibited the ability of self-renewal and invasion along with the expression of cancer stem cell-related genes in BCSCs. Moreover, CD44s knockdown inhibited the tumorigenesis ability in vivo.Conclusion: Our findings revealed that CD44s is the predominant isoform expressed in BCSCs, and is an important molecule for maintaining the properties of BCSCs. Targeting CD44s in BCSCs may be a potential new direction for breast cancer treatment.

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High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma

Genes ◽

10.3390/genes12091373 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1373

Author(s):

Melanie Generali ◽

Sampoorna Satheesha ◽

Peter K. Bode ◽

Debora Wanner ◽

Beat W. Schäfer ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

High Frequency ◽

Cell Clone ◽

Hierarchical Organization ◽

Stem Cell Markers ◽

Worse Prognosis

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Fusion-positive RMS (FPRMS), expressing the PAX3/7-FOXO1, has a worse prognosis compared to the more common fusion-negative RMS (FNRMS). Although several studies reported hierarchical organization for FNRMS with the identification of cancer stem cells, the cellular organization of FPRMS is not yet clear. In this study we investigated the expression of key stem cell markers, developed a sphere assay, and investigated the seven most common FPRMS cell lines for subpopulations of tumor propagating cancer stem-like cells, also called cancer stem cells (CSCs). Moreover, loss- and gain-of-functions of the stem cell genes SOX2, OCT4, and NANOG were investigated in the same cells. Single-cell clonal analysis was performed in vitro as well as in vivo. We found that no stable CSC subpopulation could be enriched in FPRMS. Unlike depletion of PAX3-FOXO1, neither overexpression nor siRNA-mediated downregulation of SOX2, OCT4, and NANOG affected physiology of RMS cells. Every single subclone-derived cell clone initiated tumor growth in mice, despite displaying considerable heterogeneity in gene expression. FPRMS appears to contain a high frequency of tumor propagating stem-like cells, which could explain their higher propensity for metastasis and relapse. Their dependency on PAX3-FOXO1 activity reinforces the importance of the fusion protein as the key therapeutic target.

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Resident Stem Cells and Renal Carcinoma

International Journal of Nephrology ◽

10.4061/2011/286985 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Benedetta Bussolati ◽

Alessia Brossa ◽

Giovanni Camussi

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Renal Carcinoma ◽

Stem Cell Population ◽

Self Renewal ◽

Resident Stem Cells ◽

Renal Cancer Stem Cells

According to the cancer stem cell hypothesis tumors are maintained by a cancer stem cell population which is able to initiate and maintain tumors. Tumor-initiating stem cells display stem or progenitor cell properties such as self-renewal and capacity to re-establish tumors that recapitulate the tumor of origin. In this paper, we discuss data relative to the presence of cancer stem cells in human renal carcinoma and their possible origin from normal resident stem cells. The cancer stem cells identified in human renal carcinomas are not derived from the normal CD133+progenitors of the kidney, but rather from a more undifferentiated population that retains a mesenchymal phenotype. This population is able to self-renewal, clonogenicity, and in vivo tumor initiation. Moreover, they retain pluripotent differentiation capability, as they can generate not only the epithelial component of the tumor, but also tumor endothelial cells. This suggests that renal cancer stem cells may contribute to the intratumor vasculogenesis.

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Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666181002151330 ◽

2019 ◽

Vol 14 (5) ◽

pp. 428-436 ◽

Cited By ~ 4

Author(s):

Gabriele D. Bigoni-Ordóñez ◽

Daniel Czarnowski ◽

Tyler Parsons ◽

Gerard J. Madlambayan ◽

Luis G. Villa-Diaz

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

The Self ◽

Self Renewal ◽

Terminal Disease

Cancer is a highly prevalent and potentially terminal disease that affects millions of individuals worldwide. Here, we review the literature exploring the intricacies of stem cells bearing tumorigenic characteristics and collect evidence demonstrating the importance of integrin α6 (ITGA6, also known as CD49f) in cancer stem cell (CSC) activity. ITGA6 is commonly used to identify CSC populations in various tissues and plays an important role sustaining the self-renewal of CSCs by interconnecting them with the tumorigenic microenvironment.

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A reactive oxygen species-generating, cyclooxygenase-2 inhibiting, cancer stem cell-potent tetranuclear copper(ii) cluster

Dalton Transactions ◽

10.1039/c7dt02789c ◽

2017 ◽

Vol 46 (38) ◽

pp. 12785-12789 ◽

Cited By ~ 26

Author(s):

C. Lu ◽

K. Laws ◽

A. Eskandari ◽

K. Suntharalingam

Keyword(s):

Reactive Oxygen Species ◽

Stem Cells ◽

Schiff Base ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Reactive Oxygen ◽

Cyclooxygenase 2 ◽

Oxygen Species

Tetranuclear copper(ii) complexes containing multiple diclofenac and Schiff base moieties,1–4, are shown to kill bulk cancer cells and cancer stem cells (CSCs) with low micromolar potency.

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Understanding the Influence of Substrate When Growing Tumorspheres

10.21203/rs.3.rs-67713/v1 ◽

2020 ◽

Author(s):

Lucía Benítez ◽

Lucas Barberis ◽

Luciano Vellón ◽

Carlos Alberto Condat

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Growth Factors ◽

Cell Growth ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Stem Cell Niche ◽

Cell Number ◽

Hard Substrate ◽

Cell Niche

Abstract Background: Cancer stem cells are important for the development of many solid tumors. These cells receive promoting and inhibitory signals that depend on the nature of their environment (their niche) and determine cell dynamics. Mechanical stresses are crucial to the initiation and interpretation of these signals. Methods: A two-population mathematical model of tumorsphere growth is used to interpret the results of a series of experiments recently carried out in Tianjin, China, and extract information about the intraspecific and interspecific interactions between cancer stem cell and differentiated cancer cell populations. Results: The model allows us to reconstruct the time evolution of the cancer stem cell fraction, which was not directly measured. We find that, in the presence of stem cell growth factors, the interspecific cooperation between cancer stem cells and differentiated cancer cells induces a positive feedback loop that determines growth, independently of substrate hardness. In a frustrated attempt to reconstitute the stem cell niche, the number of cancer stem cells increases continuously with a reproduction rate that is enhanced by a hard substrate. For growth on soft agar, intraspecific interactions are always inhibitory, but on hard agar the interactions between stem cells are collaborative while those between differentiated cells are strongly inhibitory. Evidence also suggests that a hard substrate brings about a large fraction of asymmetric stem cell divisions. In the absence of stem cell growth factors, the barrier to differentiation is broken and overall growth is faster, even if the stem cell number is conserved. Conclusions: Our interpretation of the experimental results validates the centrality of the concept of stem cell niche when tumor growth is fueled by cancer stem cells. Niche memory is found to be responsible for the characteristic population dynamics observed in tumorspheres. A specific condition for the growth of the cancer stem cell number is also obtained.

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