Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells

Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.

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The molecular mechanisms of curcumin’s inhibitory effects on cancer stem cells

Journal of Cellular Biochemistry ◽

10.1002/jcb.27757 ◽

2018 ◽

Vol 120 (4) ◽

pp. 4739-4747 ◽

Cited By ~ 12

Author(s):

Elham Zendehdel ◽

Elham Abdollahi ◽

Amir Abbas Momtazi‐Borojeni ◽

Mitra Korani ◽

Seyedeh Hoda Alavizadeh ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Inhibitory Effects

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

Journal of Oncology ◽

10.1155/2012/376894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 44

Author(s):

Paola Brescia ◽

Cristina Richichi ◽

Giuliana Pelicci

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Large Scale ◽

Molecular Mechanisms ◽

Cell Phenotype ◽

Multiple Tumor ◽

Early Results ◽

Tumorigenic Potential ◽

Tumor Types

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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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Cancers ◽

10.3390/cancers13184550 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4550

Author(s):

Laura Gramantieri ◽

Catia Giovannini ◽

Fabrizia Suzzi ◽

Ilaria Leoni ◽

Francesca Fornari

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Anticancer Agents ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Driving Forces ◽

Predictive Biomarkers ◽

Molecular Classification ◽

Circulating Biomarkers ◽

Therapeutic Implications

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.

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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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Characterization of CD133+/CD44+ human prostate cancer stem cells with ATR-FTIR spectroscopy

The Analyst ◽

10.1039/c9an00093c ◽

2019 ◽

Vol 144 (6) ◽

pp. 2138-2149 ◽

Cited By ~ 4

Author(s):

Günnur Güler ◽

Ummu Guven ◽

Gulperi Oktem

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Ftir Spectroscopy ◽

Molecular Mechanisms ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Stem Cells

Molecular mechanisms and features of prostate cancer stem cells, which are crucial for improving target specific therapies, were elucidated with ATR-FTIR spectroscopy.

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Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

Cancers ◽

10.3390/cancers12092482 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2482

Author(s):

Samson Mathews Samuel ◽

Elizabeth Varghese ◽

Lenka Koklesová ◽

Alena Líšková ◽

Peter Kubatka ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Acquired Resistance ◽

Breast Cancers ◽

Intrinsic Resistance ◽

Mesenchymal Transition ◽

Cancer Breast

Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.

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Low CD8+ T Cell Infiltration and High PD-L1 Expression Are Associated with Level of CD44+/CD133+ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer

Cancers ◽

10.3390/cancers11040541 ◽

2019 ◽

Vol 11 (4) ◽

pp. 541 ◽

Cited By ~ 20

Author(s):

Ya-Chin Hou ◽

Ying-Jui Chao ◽

Min-Hua Hsieh ◽

Hui-Ling Tung ◽

Hao-Chen Wang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

T Cells ◽

Cancer Stem Cells ◽

Cd8 T Cells ◽

Death Receptor ◽

Recurrence Risk ◽

Immune Checkpoints ◽

Prognostic Effect ◽

A Minor

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effects to evade immune system recognition. However, the clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, high infiltration of CD8+ T cells could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.

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Cancer Stem Cells in Brain Tumor Biology

Cold Spring Harbor Symposia on Quantitative Biology ◽

10.1101/sqb.2008.73.060 ◽

2008 ◽

Vol 73 (0) ◽

pp. 411-420 ◽

Cited By ~ 56

Author(s):

J.N. Rich ◽

C.E. Eyler

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Cancer Stem Cells ◽

Tumor Biology

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Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells

Nutrients ◽

10.3390/nu12061798 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1798 ◽

Cited By ~ 5

Author(s):

Mariarosaria Negri ◽

Annalisa Gentile ◽

Cristina de Angelis ◽

Tatiana Montò ◽

Roberta Patalano ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Vitamin D ◽

Drug Resistance ◽

Cancer Therapy ◽

Cancer Stem Cells ◽

Crucial Role ◽

Molecular Mechanisms ◽

Vitamin D Supplementation

Increasing interest in studying the role of vitamin D in cancer has been provided by the scientific literature during the last years, although mixed results have been reported. Vitamin D deficiency has been largely associated with various types of solid and non-solid human cancers, and the almost ubiquitous expression of vitamin D receptor (VDR) has always led to suppose a crucial role of vitamin D in cancer. However, the association between vitamin D levels and the risk of solid cancers, such as colorectal, prostate and breast cancer, shows several conflicting results that raise questions about the use of vitamin D supplements in cancer patients. Moreover, studies on vitamin D supplementation do not always show improvements in tumor progression and mortality risk, particularly for prostate and breast cancer. Conversely, several molecular studies are in agreement about the role of vitamin D in inhibiting tumor cell proliferation, growth and invasiveness, cell cycle arrest and inflammatory signaling, through which vitamin D may also regulate cancer microenvironment through the activation of different molecular pathways. More recently, a role in the regulation of cancer stem cells proliferation and short non-coding microRNA (miRNAs) expression has emerged, conferring to vitamin D a more crucial role in cancer development and progression. Interestingly, it has been shown that vitamin D is able not only to potentiate the effects of traditional cancer therapy but can even contribute to overcome the molecular mechanisms of drug resistance—often triggering tumor-spreading. At this regard, vitamin D can act at various levels through the regulation of growth of cancer stem cells and the epithelial–mesenchymal transition (EMT), as well as through the modulation of miRNA gene expression. The current review reconsiders epidemiological and molecular literature concerning the role of vitamin D in cancer risk and tumor development and progression, as well as the action of vitamin D supplementation in potentiating the effects of drug therapy and overcoming the mechanisms of resistance often triggered during cancer therapies, by critically addressing strengths and weaknesses of available data from 2010 to 2020.

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