Current Strategies for Identification of Glioma Stem Cells: Adequate or Unsatisfactory?

Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge.

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HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1520032112 ◽

2015 ◽

Vol 112 (45) ◽

pp. E6215-E6223 ◽

Cited By ~ 122

Author(s):

Huimin Zhang ◽

Haiquan Lu ◽

Lisha Xiang ◽

John W. Bullen ◽

Chuanzhao Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Cell Phenotype

Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.

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Graphene oxide selectively targets cancer stem cells, across multiple tumor types: Implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”

Oncotarget ◽

10.18632/oncotarget.3348 ◽

2015 ◽

Vol 6 (6) ◽

pp. 3553-3562 ◽

Cited By ~ 102

Author(s):

Marco Fiorillo ◽

Andrea F. Verre ◽

Maria Iliut ◽

Maria Peiris-Pagés ◽

Bela Ozsvari ◽

...

Keyword(s):

Stem Cells ◽

Graphene Oxide ◽

Cancer Stem Cells ◽

Cancer Treatment ◽

Multiple Tumor ◽

Tumor Types

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Stem Cell Concept in Thyroid Cancer

Integrative Journal of Medical Sciences ◽

10.15342/ijms.7.199 ◽

2020 ◽

Vol 7 ◽

Author(s):

Cihan Zamur ◽

Uğur Topal ◽

Harun Özdemir ◽

Serdar Altınay

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Thyroid Cancer ◽

Thyroid Gland ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Clinical Results ◽

Cell Populations ◽

Cellular Origin ◽

Rare Cells

The most frequently diagnosed endocrine cancer, which causes more deaths than any other endocrine cancer, is thyroid cancer. Cancer stem cells are rare cells found in tumors that can regenerate themselves, phenotypically leads to various tumor cell populations and trigger tumorigenesis. Cancer stem cells have been identified in many cancers, including thyroid cancer. Having an understanding of the molecular mechanisms which control the biology of cancer stem cells and the disease processes will help us in designing more rational targeted therapies for aggressive thyroid cancers. In this review, we aimed to present the current accepted knowledge about thyroid stem cells, information regarding the cellular origin of thyroid cancer stem cells, and the clinical results of cancer stem cells present in the thyroid gland.

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Cancer stem cells: a new approach to tumor development

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.61.01.086 ◽

2015 ◽

Vol 61 (1) ◽

pp. 86-93 ◽

Cited By ~ 7

Author(s):

Natália Cristina Ciufa Kobayashi ◽

Samuel Marcos Ribeiro de Noronha

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Tumor Cell ◽

Cancer Cells ◽

Cell Cancer ◽

Tumor Development ◽

New Approach ◽

Tumor Types ◽

Immunosuppressed Mice

Many theories have been proposed to explain the origins of cancer. Currently, evidences show that not every tumor cell is capable of initiating a tumor. Only a small part of the cancer cells, called cancer stem cells (CSCs), can generate a tumor identical to the original one, when removed from human tumors and transplanted into immunosuppressed mice. The name given to these cells comes from the resemblance to normal stem cells, except for the fact that their ability to divide is infinite. These cells are also affected by their microenvironment. Many of the signaling pathways, such as Wnt, Notch and Hedgehog, are altered in this tumoral subpopulation, which also contributes to abnormal proliferation. Researchers have found several markers for CSCs; however, much remains to be studied, or perhaps a universal marker does not even exist, since they vary among tumor types and even from patient to patient. It was also found that cancer stem cells are resistant to radiotherapy and chemotherapy. This may explain the re-emergence of the disease, since they are not completely eliminated and minimal amounts of CSCs can repopulate a tumor. Once the diagnosis in the early stages greatly increases the chances of curing cancer, identifying CSCs in tumors is a goal for the development of more effective treatments. The objective of this article is to discuss the origin of cancer according to the theory of stem cell cancer, as well as its markers and therapies used for treatment.

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Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment

Stem Cells International ◽

10.1155/2017/2925869 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 54

Author(s):

Jeffrey Koury ◽

Li Zhong ◽

Jijun Hao

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Treatment ◽

Signaling Pathways ◽

Small Subset ◽

Self Renewal ◽

Multiple Tumor ◽

Notch Pathways ◽

Tumor Types ◽

Heterogeneous Tumor

The Wnt, Hedgehog, and Notch pathways are inherent signaling pathways in normal embryogenesis, development, and hemostasis. However, dysfunctions of these pathways are evident in multiple tumor types and malignancies. Specifically, aberrant activation of these pathways is implicated in modulation of cancer stem cells (CSCs), a small subset of cancer cells capable of self-renewal and differentiation into heterogeneous tumor cells. The CSCs are accountable for tumor initiation, growth, and recurrence. In this review, we focus on roles of Wnt, Hedgehog, and Notch pathways in CSCs’ stemness and functions and summarize therapeutic studies targeting these pathways to eliminate CSCs and improve overall cancer treatment outcomes.

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Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

Oncotarget ◽

10.18632/oncotarget.3174 ◽

2015 ◽

Vol 6 (7) ◽

pp. 4569-4584 ◽

Cited By ~ 223

Author(s):

Rebecca Lamb ◽

Bela Ozsvari ◽

Camilla L. Lisanti ◽

Herbert B. Tanowitz ◽

Anthony Howell ◽

...

Keyword(s):

Infectious Disease ◽

Stem Cells ◽

Cancer Stem Cells ◽

Multiple Tumor ◽

Tumor Types

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Estimating stem cell fractions in hierarchically organized tumors

10.1101/013672 ◽

2015 ◽

Author(s):

Benjamin Werner ◽

Jacob G Scott ◽

Andrea Sottoriva ◽

Alexander RA Anderson ◽

Arne Traulsen ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Tumor Growth ◽

Treatment Strategies ◽

Exact Result ◽

Growth Patterns ◽

Cell Fractions ◽

Tumor Types

Cancers arise as a result of genetic and epigenetic alterations. These accumulate in cells during the processes of tissue development, homeostasis and repair. Many tumor types are hierarchically organized and driven by a sub-population of cells often called cancer stem cells. Cancer stem cells are uniquely capable of recapitulating the tumor and can be highly resistant to radio- and chemotherapy treatment. We investigate tumor growth patterns from a theoretical standpoint and show how significant changes in pre- and post-therapy tumor dynamics are tied to the dynamics of cancer stem cells. We identify two characteristic growth regimes of a tumor population that can be leveraged to estimate cancer stem cell fractions in vivo using simple linear regression. Our method is a mathematically exact result, parameter free and does not require any microscopic knowledge of the tumor properties. A more accurate quantification of the direct link between the sub-population driving tumor growth and treatment response promises new ways to individualize treatment strategies.

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STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.088 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi23-vi24

Author(s):

Kelly Mitchell ◽

Joseph Alvarado ◽

Christopher Goins ◽

Steven Martinez ◽

Jonathan Macdonald ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Transcription Factors ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Self Renewal ◽

Stem Cell Maintenance ◽

Cell Maintenance

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.

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A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

Frontiers in Oncology ◽

10.3389/fonc.2021.689839 ◽

2021 ◽

Vol 11 ◽

Author(s):

Mahdi Abdoli Shadbad ◽

Negar Hosseinkhani ◽

Zahra Asadzadeh ◽

Afshin Derakhshani ◽

Noora Karim Ahangar ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cell Phenotype ◽

Stem Cell Markers ◽

Advanced Tumor Stage

As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44+CD24-/low as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44+CD24-/low phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44+CD24-/low phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44+CD24-/low phenotype can be utilized to determine TNBC patients’ prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.

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Pituitary Remodeling Throughout Life: Are Resident Stem Cells Involved?

Frontiers in Endocrinology ◽

10.3389/fendo.2020.604519 ◽

2021 ◽

Vol 11 ◽

Author(s):

Emma Laporte ◽

Annelies Vennekens ◽

Hugo Vankelecom

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Pituitary Gland ◽

Molecular Mechanisms ◽

Pituitary Function ◽

Cell Phenotype ◽

Cell Populations ◽

Cell Remodeling

The pituitary gland has the primordial ability to dynamically adapt its cell composition to changing hormonal needs of the organism throughout life. During the first weeks after birth, an impressive growth and maturation phase is occurring in the gland during which the distinct hormonal cell populations expand. During pubertal growth and development, growth hormone (GH) levels need to peak which requires an adaptive enterprise in the GH-producing somatotrope population. At aging, pituitary function wanes which is associated with organismal decay including the somatopause in which GH levels drop. In addition to these key time points of life, the pituitary’s endocrine cell landscape plastically adapts during specific (patho-)physiological conditions such as lactation (need for PRL) and stress (engagement of ACTH). Particular resilience is witnessed after physical injury in the (murine) gland, culminating in regeneration of destroyed cell populations. In many other tissues, adaptive and regenerative processes involve the local stem cells. Over the last 15 years, evidence has accumulated that the pituitary gland houses a resident stem cell compartment. Recent studies propose their involvement in at least some of the cell remodeling processes that occur in the postnatal pituitary but support is still fragmentary and not unequivocal. Many questions remain unsolved such as whether the stem cells are key players in the vivid neonatal growth phase and whether the decline in pituitary function at old age is associated with decreased stem cell fitness. Furthermore, the underlying molecular mechanisms of pituitary plasticity, in particular the stem cell-linked ones, are still largely unknown. Pituitary research heavily relies on transgenic in vivo mouse models. While having proven their value, answers to pituitary stem cell-focused questions may more diligently come from a novel powerful in vitro research model, termed organoids, which grow from pituitary stem cells and recapitulate stem cell phenotype and activation status. In this review, we describe pituitary plasticity conditions and summarize what is known on the involvement and phenotype of pituitary stem cells during these pituitary remodeling events.

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