How Can We Overcome Radiation Induced Recruitment of Cancer Stem Cells Under Chronic Hypoxia: Contribution of Fraction Dose Size As a Key Factor

Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key messenger in intercellular communication in the TME. Exosomes are small double-layered lipid extracellular vesicles that can carry a variety of molecules, including proteins, lipids, and nucleic acids. Exosomal miRNA released by cancer cells can mediate phenotypical changes in the cells of TME to promote tumor growth and therapy resistance, for example, fibroblast- and macrophages-induced differentiation. Cancer stem cells can transfer and enhance drug resistance in neighboring sensitive cancer cells by releasing exosomal miRNAs that target antiapoptotic and immune-suppressive pathways. Exosomes induce drug resistance by carrying ABC transporters, which export chemotherapeutic agents out of the recipient cells, thereby reducing the drug concentration to suboptimal levels. Exosome biogenesis inhibitors represent a promising adjunct therapeutic approach in cancer therapy to avoid the acquisition of a resistant phenotype. In conclusion, exosomal miRNAs play a crucial role in the TME to confer drug resistance and survivability to tumor cells, and we also highlight the need for further investigations in this promising field.

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Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22179280 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9280

Author(s):

Hilal Arnouk ◽

Gloria Yum ◽

Dean Shah

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Cancer Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Malignant Tumors ◽

Lymphatic Vessels ◽

Mesenchymal Phenotype ◽

Mesenchymal Transition ◽

Skin Cancers ◽

Key Factor

Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed epithelial cells into a more mobile mesenchymal phenotype through the downregulation of epithelial adhesion molecules such as E-cadherin, occludins, and claudins, and the upregulation of mesenchymal, mobile proteins, such as N-cadherin, Snail, and Slug. Consequently, Cripto-1’s role in inducing EMT to promote cell motility is beneficial in embryogenesis, but detrimental in the formation, progression and metastasis of malignant tumors. Indeed, Cripto-1 is found to be upregulated in most cancers, such as breast, lung, gastrointestinal, hepatic, renal, cervical, ovarian, prostate, and skin cancers. Through its role in EMT, Cripto-1 can remodel cancer cells to enable them to travel through the extracellular matrix as well as blood and lymphatic vessels to metastasize to different organs. Additionally, Cripto-1 promotes the survival of cancer stem cells, which can lead to relapse in cancer patients.

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Abstract 5149: Nucleostemin is a key factor in maintenance of human glioblastoma-derived cancer stem cells

10.1158/1538-7445.am10-5149 ◽

2010 ◽

Author(s):

Marta L. Izquierdo ◽

Jon Gil

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Human Glioblastoma ◽

Key Factor

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Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Journal of Experimental Medicine ◽

10.1084/jem.20142288 ◽

2015 ◽

Vol 212 (12) ◽

pp. 2057-2075 ◽

Cited By ~ 41

Author(s):

Aurélie Ladang ◽

Francesca Rapino ◽

Lukas C. Heukamp ◽

Lars Tharun ◽

Kateryna Shostak ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Ex Vivo ◽

Tumor Initiation ◽

Normal Epithelium ◽

Intestinal Epithelia ◽

Protein Levels ◽

Radiation Induced ◽

Sox9 Protein

Tumor initiation in the intestine can rapidly occur from Lgr5+ crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5+/Dclk1+/Sox9+ cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5+ cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5+/Dclk1+/Sox9+ cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5+/Dclk1+ cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1+ cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.

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