Role of hypoxia inducible factor-1 in cancer stem cells (Review)

In cancers, hypoxia inducible factor 1 (HIF-1) is an over-expressed transcription factor, which regulates a large set of genes involved in tumour vascularization, metastases, and cancer stem cells (CSCs) formation and self-renewal.

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Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression

International Journal of Molecular Sciences ◽

10.3390/ijms21082660 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2660

Author(s):

Marco Papale ◽

Mariachiara Buccarelli ◽

Cristiana Mollinari ◽

Matteo A. Russo ◽

Roberto Pallini ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Hypoxia Inducible Factor ◽

Human Tumor ◽

Metastatic Potential ◽

Cellular Adhesion ◽

Brain Invasion ◽

Hypoxia Inducible Factor 1 ◽

Tumor Tissues

Tumor hypoxic microenvironment causes hypoxia inducible factor 1 alpha (HIF-1α) activation and necrosis with alarmins release. Importantly, HIF-1α also controls the expression of alarmin receptors in tumor cells that can bind to and be activated by alarmins. Human tumor tissues possess 1–2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of tumors. Our hypothesis is that hypoxic CSCs express alarmin receptors that can bind alarmins released during necrosis, an event favoring CSCs migration. To investigate this aspect, glioblastoma stem-like cell (GSC) lines were kept under hypoxia to determine the expression of hypoxic markers as well as receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1α inhibition by digoxin or acriflavine prevented the response of GSCs to hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that hypoxia is important not only for GSCs maintenance but also for guiding their response to external necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by glioblastoma stem cells (GSCs).

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Role of Tumor Microenvironment in Cancer Stem Cells Resistance to Radiotherapy

Current Cancer Drug Targets ◽

10.2174/1568009622666211224154952 ◽

2021 ◽

Vol 22 ◽

Author(s):

Shahram Taeb ◽

Milad Ashrafizadeh ◽

Ali Zarrabi ◽

Saeed Rezapoor ◽

Ahmed Eleojo Musa ◽

...

Keyword(s):

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Immune Responses ◽

Immune Cells ◽

Stromal Cells ◽

Hypoxia Inducible Factor ◽

Proliferation Capacity ◽

Chronic Disorder

Abstract: Cancer is a chronic disorder that involves several elements of both the tumor and the host stromal cells. At present, the complex relationship between the various factors presents in the tumor microenvironment (TME) and tumor cells, as well as immune cells located within the TME, is still poorly known. Within the TME, the crosstalk of these factors and immune cells essentially determines how a tumor reacts to the treatment and how the tumor can ultimately be destroyed, remain dormant, or develop and metastasize. Also, in TME, reciprocal crosstalk between cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), hypoxia-inducible factor (HIF) intensifies the proliferation capacity of cancer stem cells (CSCs). CSCs are subpopulation of cells that reside within the tumor bulk and have the capacity to self-renew, differentiate, and repair DNA damage. These characteristics make CSCs develop resistance to a variety of treatments, such as radiotherapy (RT). RT is a frequent and often curative treatment for local cancer which mediates tumor elimination by cytotoxic actions. Also, cytokines and growth factors that are released into TME, have been involved in the activation of tumor radioresistance and the induction of different immune cells, altering local immune responses. In this review, we discuss the pivotal role of TME in resistance of CSCs to RT.

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Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs

Cancers ◽

10.3390/cancers13071674 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1674

Author(s):

Sara Tomei ◽

Ola Ibnaof ◽

Shilpa Ravindran ◽

Soldano Ferrone ◽

Cristina Maccalli

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Immune Responses ◽

Antigen Processing ◽

Aberrant Expression ◽

Immunological Profile ◽

Malignant Lesions ◽

Novel Therapeutic Strategies ◽

Antigen Processing And Presentation

Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.

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

Cancers ◽

10.3390/cancers13061239 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1239

Author(s):

Leila Jahangiri ◽

Tala Ishola ◽

Perla Pucci ◽

Ricky M. Trigg ◽

Joao Pereira ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Regulatory Networks ◽

Epithelial To Mesenchymal Transition ◽

Tumour Microenvironment ◽

Repair Capacity ◽

Mesenchymal Transition ◽

Cellular Processes

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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Glioma Revisited: From Neurogenesis and Cancer Stem Cells to the Epigenetic Regulation of the Niche

Journal of Oncology ◽

10.1155/2012/537861 ◽

2012 ◽

Vol 2012 ◽

pp. 1-20 ◽

Cited By ~ 17

Author(s):

Felipe de Almeida Sassi ◽

Algemir Lunardi Brunetto ◽

Gilberto Schwartsmann ◽

Rafael Roesler ◽

Ana Lucia Abujamra

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cellular Proliferation ◽

Survival Rates ◽

Comprehensive Analysis ◽

Heterogeneous Population ◽

Aggressive Tumor ◽

Epigenetic Modulation ◽

The Brain

Gliomas are the most incident brain tumor in adults. This malignancy has very low survival rates, even when combining radio- and chemotherapy. Among the gliomas, glioblastoma multiforme (GBM) is the most common and aggressive type, and patients frequently relapse or become refractory to conventional therapies. The fact that such an aggressive tumor can arise in such a carefully orchestrated organ, where cellular proliferation is barely needed to maintain its function, is a question that has intrigued scientists until very recently, when the discovery of the existence of proliferative cells in the brain overcame such challenges. Even so, the precise origin of gliomas still remains elusive. Thanks to new advents in molecular biology, researchers have been able to depict the first steps of glioma formation and to accumulate knowledge about how neural stem cells and its progenitors become gliomas. Indeed, GBM are composed of a very heterogeneous population of cells, which exhibit a plethora of tumorigenic properties, supporting the presence of cancer stem cells (CSCs) in these tumors. This paper provides a comprehensive analysis of how gliomas initiate and progress, taking into account the role of epigenetic modulation in the crosstalk of cancer cells with their environment.

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Role of p38γ MAPK in regulation of EMT and cancer stem cells

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2018.08.024 ◽

2018 ◽

Vol 1864 (11) ◽

pp. 3605-3617 ◽

Cited By ~ 12

Author(s):

Mei Xu ◽

Siying Wang ◽

Yongchao Wang ◽

Huaxun Wu ◽

Jacqueline A. Frank ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells

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The role of steroid hormones in breast cancer stem cells

Endocrine Related Cancer ◽

10.1530/erc-15-0350 ◽

2015 ◽

Vol 22 (6) ◽

pp. T177-T186 ◽

Cited By ~ 21

Author(s):

Bruno M Simões ◽

Denis G Alferez ◽

Sacha J Howell ◽

Robert B Clarke

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Steroid Hormones ◽

Normal Mammary Gland ◽

Breast Cancer Stem Cells ◽

Tumor Initiating Cells ◽

Unit Of Selection ◽

Selection For

Breast cancer stem cells (BCSCs) are potent tumor-initiating cells in breast cancer, the most common cancer among women. BCSCs have been suggested to play a key role in tumor initiation which can lead to disease progression and formation of metastases. Moreover, BCSCs are thought to be the unit of selection for therapy-resistant clones since they survive conventional treatments, such as chemotherapy, irradiation, and hormonal therapy. The importance of the role of hormones for both normal mammary gland and breast cancer development is well established, but it was not until recently that the effects of hormones on BCSCs have been investigated. This review will discuss recent studies highlighting how ovarian steroid hormones estrogen and progesterone, as well as therapies against them, can regulate BCSC activity.

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