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

2015 ◽  
Vol 212 (12) ◽  
pp. 2057-2075 ◽  
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.

scholarly journals Radiation-induced toxicity in rectal epithelial stem cell contributes to acute radiation injury in rectum

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Felipe Rodriguez Tirado ◽  
Payel Bhanja ◽  
Eduardo Castro-Nallar ◽  
Ximena Diaz Olea ◽  
Catalina Salamanca ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Cre Recombinase ◽  
Lineage Tracing ◽  
Common Side Effect ◽  
Rectal Injury ◽  
Male Mice ◽  
Pelvic Irradiation ◽  
Pelvic Malignancies ◽  
Radiation Induced

Abstract Background Radiation-induced rectal epithelial damage is a very common side effect of pelvic radiotherapy and often compromise the life quality and treatment outcome in patients with pelvic malignancies. Unlike small bowel and colon, effect of radiation in rectal stem cells has not been explored extensively. Here we demonstrate that Lgr5-positive rectal stem cells are radiosensitive and organoid-based transplantation of rectal stem cells mitigates radiation damage in rectum. Methods C57Bl6 male mice (JAX) at 24 h were exposed to pelvic irradiation (PIR) to determine the radiation effect in pelvic epithelium. Effect of PIR on Lgr5-positive rectal stem cells (RSCs) was determined in Lgr5-EGFP-Cre-ERT2 mice exposed to PIR. Effect of PIR or clinically relevant fractionated PIR on regenerative response of Lgr5-positive RSCs was examined by lineage tracing assay using Lgr5-eGFP-IRES-CreERT2; Rosa26-CAG-tdTomato mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from Lgr5-EGFP-Cre-ERT2 mice. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Organoids from Lgr5-EGFP-ires-CreERT2-TdT mice were transplanted in C57Bl6 male mice exposed to PIR. Engraftment and repopulation of Lgr5-positive RSCs were determined after tamoxifen administration to activate Cre recombinase in recipient mice. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test. Result Exposure to pelvic irradiation significantly damaged rectal epithelium with the loss of Lgr5+ve rectal stem cells. Radiosensitivity of rectal epithelium was also observed with exposure to clinically relevant fractionated pelvic irradiation. Regenerative capacity of Lgr5+ve rectal stem cells was compromised in response to fractionated pelvic irradiation. Ex vivo organoid study demonstrated that Lgr5+ve rectal stem cells are sensitive to both single and fractionated radiation. Organoid-based transplantation of Lgr5+ve rectal stem cells promotes repair and regeneration of rectal epithelium. Conclusion Lgr5-positive rectal stem cells are radiosensitive and contribute to radiation-induced rectal epithelial toxicity. Transplantation of Lgr5-positive rectal stem cells mitigates radiation-induced rectal injury and promotes repair and regeneration process in rectum.

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

Cancers ◽  
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.

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

Cancers ◽  
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.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-20 ◽  
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.

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

2018 ◽  
Vol 1864 (11) ◽  
pp. 3605-3617 ◽  
Author(s):  
Mei Xu ◽  
Siying Wang ◽  
Yongchao Wang ◽  
Huaxun Wu ◽  
Jacqueline A. Frank ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells

scholarly journals The role of steroid hormones in breast cancer stem cells

2015 ◽  
Vol 22 (6) ◽  
pp. T177-T186 ◽  
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.

Abstract 1083: A novel role of SRC in mediating bypass resistance to MEK inhibition in colorectal cancer stem cells

2021 ◽  
Author(s):  
Mingli Yang ◽  
Thomas B. Davis B. Davis ◽  
Michael V. Nebozhyn ◽  
Andrey Loboda ◽  
Heiman Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Mek Inhibition ◽  
Colorectal Cancer Stem Cells

The role of children's bone marrow mesenchymal stromal cells in the ex vivo expansion of autologous and allogeneic hematopoietic stem cells

2015 ◽  
Vol 39 (10) ◽  
pp. 1099-1110 ◽  
Author(s):  
Iordanis Pelagiadis ◽  
Eftichia Stiakaki ◽  
Christianna Choulaki ◽  
Maria Kalmanti ◽  
Helen Dimitriou
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Hematopoietic Stem

Deciphering the signaling pathways of cancer stem cells of glioblastoma multiforme: Role of Akt/mTOR and MAPK pathways

2011 ◽  
Vol 51 (1) ◽  
pp. 164-170 ◽  
Author(s):  
Meena Jhanwar-Uniyal ◽  
Ladislau Albert ◽  
Elise McKenna ◽  
Michael Karsy ◽  
Priya Rajdev ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioblastoma Multiforme ◽  
Cancer Stem Cells ◽  
Signaling Pathways ◽  
Mapk Pathways
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