The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

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Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Cancers ◽

10.3390/cancers11081058 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1058 ◽

Cited By ~ 10

Author(s):

Gener ◽

Rafael ◽

Seras-Franzoso ◽

Perez ◽

Pindado ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Distant Metastases ◽

Metastatic Potential ◽

Phenotypic Change ◽

Primary Tumors ◽

Mesenchymal Transition

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

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Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: Potential role of hypoxia

Cancer Letters ◽

10.1016/j.canlet.2012.11.019 ◽

2013 ◽

Vol 341 (1) ◽

pp. 63-72 ◽

Cited By ~ 124

Author(s):

Delphine Tamara Marie-Egyptienne ◽

Ines Lohse ◽

Richard Peter Hill

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Potential Role ◽

Mesenchymal Transition

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Abstract A039: The role of long noncoding RNAs in epithelial to mesenchymal transition and cancer stem cells

10.1158/1557-3125.advbc-a039 ◽

2013 ◽

Author(s):

Jason I. Herschkowitz ◽

Cristian Coarfa ◽

Aleix Prat ◽

Michael J. Toneff ◽

Katherine A. Hoadley ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Mesenchymal Transition

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Communication Between Epithelial–Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression

Frontiers in Oncology ◽

10.3389/fonc.2021.617597 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaobo Zheng ◽

Fuzhen Dai ◽

Lei Feng ◽

Hong Zou ◽

Li Feng ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Epithelial Mesenchymal Transition ◽

Current Knowledge ◽

Mesenchymal Transition ◽

Binary Model ◽

Epithelial Phenotype

The epithelial–mesenchymal transition (EMT) is closely associated with the acquisition of aggressive traits by carcinoma cells and is considered responsible for metastasis, relapse, and chemoresistance. Molecular links between the EMT and cancer stem cells (CSCs) have indicated that EMT processes play important roles in the expression of CSC-like properties. It is generally thought that EMT-related transcription factors (EMT-TFs) need to be downregulated to confer an epithelial phenotype to mesenchymal cells and increase cell proliferation, thereby promoting metastasis formation. However, the genetic and epigenetic mechanisms that regulate EMT and CSC activation are contradictory. Emerging evidence suggests that EMT need not be a binary model and instead a hybrid epithelial/mesenchymal state. This dynamic process correlates with epithelial–mesenchymal plasticity, which indicates a contradictory role of EMT during cancer progression. Recent studies have linked the epithelial–mesenchymal plasticity and stem cell-like traits, providing new insights into the conflicting relationship between EMT and CSCs. In this review, we examine the current knowledge about the interplay between epithelial–mesenchymal plasticity and CSCs in cancer biology and evaluate the controversies and future perspectives. Understanding the biology of epithelial–mesenchymal plasticity and CSCs and their implications in therapeutic treatment may provide new opportunities for targeted intervention.

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The microRNA-200 family: still much to discover

BioMolecular Concepts ◽

10.1515/bmc-2016-0020 ◽

2016 ◽

Vol 7 (5-6) ◽

pp. 311-319 ◽

Cited By ~ 34

Author(s):

Daniel Senfter ◽

Sibylle Madlener ◽

Georg Krupitza ◽

Robert M. Mader

Keyword(s):

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Potential Role ◽

Predictive Biomarker ◽

Mesenchymal Transition ◽

Cellular Processes ◽

Active Regulation ◽

The Individual ◽

Open Issues

AbstractIn the last decade, microRNAs (miRs or miRNAs) became of great interest in cancer research due to their multifunctional and active regulation in a variety of vital cellular processes. In this review, we discuss the miR-200 family, which is composed of five members (miR-141, miR-200a/200b/200c and miR-429). Although being among the best investigated miRNAs in the field, there are still many open issues. Here, we describe the potential role of miR-200 as prognostic and/or predictive biomarker, its influence on motility and cell migration as well as its role in epithelial to mesenchymal transition (EMT) and metastasis formation in different tumour types. Recent studies also demonstrated the influence of miR-200 on drug resistance and described a correlation between miR-200 expression levels and overall survival of patients. Despite intense research in this field, the full role of the miR-200 family in cancer progression and metastasis is not completely understood and seems to differ between different tumour types and different cellular backgrounds. To elucidate these differences further, a finer characterisation of the role of the individual miRNA-200 family members is currently under investigation.

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MiRNA-mediated EMT and CSCs in cancer chemoresistance

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00206-5 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Bing Dong ◽

Shiyu Li ◽

Shuangli Zhu ◽

Ming Yi ◽

Suxia Luo ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Therapeutic Strategy ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Complex Process ◽

Cancer Chemoresistance

AbstractCancer stem cells (CSCs) are a small group of cancer cells, which contribute to tumorigenesis and cancer progression. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) acquire the chemoresistant ability, which is regarded as an important feature of CSCs. Thus, there emerges an opinion that the generation of CSCs is considered to be driven by EMT. In this complex process, microRNAs (miRNAs) are found to play a key role. In order to overcome the drug resistance, inhibiting EMT as well as CSCs phenotype seem feasible. Thereinto, regulating the EMT- or CSCs-associated miRNAs is a crucial approach. Herein, we conduct this review to elaborate on the complicated interplay between EMT and CSCs in cancer chemoresistance, which is modulated by miRNAs. In addition, we elucidate the therapeutic strategy to overcome drug resistance through targeting EMT and CSCs.

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EMT and Stemness—Key Players in Pancreatic Cancer Stem Cells

Cancers ◽

10.3390/cancers11081136 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1136 ◽

Cited By ~ 14

Author(s):

Eva Rodriguez-Aznar ◽

Lisa Wiesmüller ◽

Bruno Sainz ◽

Patrick C. Hermann

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Progression ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Developmental Process ◽

Therapy Resistance ◽

Ductal Adenocarcinoma ◽

Mesenchymal Transition

Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression.

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