scholarly journals A2 KRT15+ TUMOR CELLS AS PUTATIVE CANCER STEM CELLS IN ESOPHAGEAL CANCER.

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 2-3
Author(s):  
J Douchin ◽  
V Giroux
Keyword(s):  
Stem Cells ◽  
Esophageal Cancer ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Treatment Resistance ◽  
Esophageal Tumor ◽  
Basal Cells ◽  
Cell Of Origin ◽  
Self Renewal

Abstract Background Esophageal cancer is a particularly deadly cancer with a 5-year survival rate of only 14% in Canada. Treatment resistance ascribed for at least 30% of the death. The acquisition of resistance to radio- and chemotherapy is mostly attributed to the presence of cancer stem cells (CSCs) and their persistence following classical treatments. CSCs are a subpopulation of tumor cells with high self-renewal and multipotent capacity which amongst others contribute to tumor heterogeneity. Our previous work identified Krt15+ esophageal cells as a rare and long-lived subpopulation of basal cells with higher self-renewal and multipotent capacities than other basal cells. Furthermore, preliminary observations suggest that Krt15+ cells could act as the cell-of-origin for ESCC, the most prevalent type of esophageal cancer worldwide. Though, we still ignore the role of Krt15+ cells in later stages of esophageal cancer such as treatment resistance and if therefore, they could act as CSC. Aims Determine if Krt15+ cells act as CSCs in ESCC patients and if they could contribute to treatment resistance. Methods To do so, we used Krt15-CrePR1;R26mT/mG mice treated with the carcinogen 4 Nitroquinoline-1-oxide (4NQO) in their drinking water for 16 weeks to induce ESCC. Twelve weeks following the beginning of 4NQO treatment, we induced Cre recombination with RU486, a PR1 agonist, leading to GFP expression specifically in Krt15+ cells. Following 4NQO treatment, mice were put back on normal water for 8 to 12 weeks allowing tumors to grow. At euthanasia, esophageal tumor cells were FACS sorted to isolate Krt15+ (GFP+) and Krt15- (GFP-) cells, which were then grown as tumoroids. Results We first validated that 4NQO successfully induced the formation of esophageal lesions in our model, which comprises Krt15+ and Krt15- tumor cells. Tumoroids were then successfully derived from these FACS-sorted cell populations. We demonstrated the increase of CSC-like cells within Krt15+ tumoroids compared to Krt15- tumoroids by measuring the presence of CD44highCD24high cells, two well-known CSC markers, by flow cytometry. Interestingly, Krt15+ and Krt15- tumoroids are histologically distinct. As observed for normal cells, Krt15+ tumoroids appeared as more multipotent and heterogenous than Krt15- tumoroids. Furthermore, Krt15+ tumoroids display higher hyperplasia than Krt15- tumoroids suggesting that Krt15+ tumor cells are functionally distinct from Krt15- tumor cells. Conclusions Krt15+ tumoroids display higher CSC content and hyperplastic capacity suggesting their potential role in esophageal cancer. With this project, we aim to highlight the role of Krt15+ cells in treatment resistance and put forward new targets to overcome this deadly issue in ESCC patients. Funding Agencies CAGCanada research chair TIER 2

Cancer stem cells

2019 ◽  
pp. 283-300
Author(s):  
Connor Sweeney ◽  
Lynn Quek ◽  
Betty Gration ◽  
Paresh Vyas
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Experimental Studies ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Self Renewal ◽  
Multipotent Stem Cells ◽  
Anticancer Chemotherapy ◽  
Normal Tissues ◽  
Oncogenic Mutation

The concept of cancer stem cells (CSCs) emerged from our understanding of the way in which normal tissues are generated from multipotent stem cells. Regenerative tissues exhibit a cellular hierarchy of differentiation, which is maintained by stem cells. Evidence from experimental models has indicated that a similar hierarchy is seen in at least some cancers, where CSCs give rise to disordered and dysfunctional tissues, leading to disease. The CSC model proposes that tumours can be divided into at least two distinct populations. The stem cells are a specialized population of cancer cells with the unique property of long-term self-renewal that maintain the growth of the cancerous clone. These stem cells give rise to the second population of cells, which form the bulk of the tumour, and lack indefinite self-renewal. Recently, our understanding of CSCs has been refined through combining genetic, epigenetic, and functional models of tumorigenesis. Malignant transformation occurs as the result of sequential acquisition of genetic mutations. Capacity for self-renewal is essential for a clone to survive and progress to become cancerous. If an oncogenic mutation occurs in a cell that is incapable of self-renewal, the clone will become exhausted through differentiation. CSCs may survive anticancer chemotherapy and increasing evidence indicates their role in mediating treatment resistance and relapse. Therefore, strategies to eradicate cancers must effectively target the stem cells that maintain their growth. CSC-directed therapeutic strategies are currently being explored in experimental studies and clinical trials but reducing toxicity to normal tissue stem cells represents a significant challenge.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

The Role of Nrf2 signaling in cancer stem cells: From stemness and self-renewal to tumorigenesis and chemoresistance

Life Sciences ◽  
2019 ◽  
Vol 239 ◽  
pp. 116986 ◽  
Author(s):  
Houman Kahroba ◽  
Masoud Shirmohamadi ◽  
Mohammad Saeid Hejazi ◽  
Nasser Samadi
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Self Renewal

scholarly journals The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies

2019 ◽  
Vol 20 (15) ◽  
pp. 3824 ◽  
Author(s):  
Larisa Ryskalin ◽  
Anderson Gaglione ◽  
Fiona Limanaqi ◽  
Francesca Biagioni ◽  
Pietro Familiari ◽  
...  
Keyword(s):  
Stem Cells ◽  
Treatment Resistance ◽  
Primary Brain Tumor ◽  
Small Subset ◽  
Self Renewal ◽  
Neuronal Stem Cells ◽  
Proliferation And Differentiation ◽  
The Common ◽  
Pluripotency Maintenance

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology.

scholarly journals Norcantharidin, Derivative of Cantharidin, for Cancer Stem Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Chen-Hsi Hsieh ◽  
K. S. Clifford Chao ◽  
Hui-Fen Liao ◽  
Yu-Jen Chen
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Treatment ◽  
Treatment Resistance ◽  
Notch Signaling Pathway ◽  
Chemotherapeutic Agents ◽  
Water Soluble ◽  
Self Renewal ◽  
Active Efflux ◽  
Effective Strategies

Cancer stem cells (CSCs) existing in human cancers have been demonstrated to be a major cause of cancer treatment resistance, invasion, metastasis, and relapse. Self-renewal pathways, Wnt/β-catenin, Sonic hedgehog (Shh), and the Notch signaling pathway play critical roles in developing CSCs and lead to angiogenesis, migration, invasion, and metastasis. Multidrug resistance (MDR) is an unfavorable factor causing the failure of treatments against cancer cells. The most important and thoroughly studied mechanism involved in MDR is the active efflux of chemotherapeutic agents through membrane drug transporters. There is growing evidence that Norcantharidin (NCTD), a water-soluble synthetic small molecule derivative of naturally occurring cantharidin from the medicinal insect blister beetle (Mylabris phalerataPallas), is capable of chemoprevention and tumor inhibition. We summarize investigations into the modulation of self-renewal pathways and MDR in CSCs by NCTD. This review may aid in further investigation of using NCTD to develop more effective strategies for cancer treatment to reduce resistance and recurrence.

scholarly journals Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells

2016 ◽  
Vol 48 (8) ◽  
pp. e255-e255 ◽  
Author(s):  
Dae Kyoung Kim ◽  
Eun Jin Seo ◽  
Eun J Choi ◽  
Su In Lee ◽  
Yang Woo Kwon ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Crucial Role ◽  
The Self ◽  
Ovarian Cancer Stem Cells ◽  
Self Renewal

scholarly journals A149 TRP53 LOSS IN KRT15+ INTESTINAL STEM CELLS SEVERELY AFFECTS SECRETORY CELL FATE AND SELF-RENEWAL

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 141-142
Author(s):  
A Dubey ◽  
A Gonneaud ◽  
V Giroux
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Secretory Cell ◽  
Goblet Cells ◽  
Tumor Formation ◽  
Cell Of Origin ◽  
Self Renewal ◽  
Cre Recombination ◽  
Small Intestinal

Abstract Background Intestinal epithelium homeostasis is maintained by two main populations of stem cells: Lgr5+ and reserve stem cells. Under injury, cell plasticity has been observed in progenitor and differentiated cells. We recently reported that Krt15+ cells are present in small intestinal and colon epithelia, and harbor self-renewal, multipotent and regenerative capacities. As in Lgr5+and reserve stem cells, hyperactivation of Wnt/b-catenin pathway in Krt15+ stem cells lead to tumor formation in the intestinal epithelium. While these intestinal stem cell populations can act as tumor-initiating cells in sporadic colon cancer, little is known about the cell-of-origin of colitis-associated colon cancer (CAC). TP53 alteration is reported as an early event in CAC. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ stem cells will perturb the epithelial homeostasis and lead to tumor formation. Aims Identify if Krt15+ cells may act as the cell-of-origin in colitis-associated colorectal cancer Methods To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15-CrePR1;Trp53fl/fl (Krt15△Trp53) mice, induced Cre recombination by injecting RU486 (PR agonist) and euthanized the mice at different time points following recombination. Results Results Twelve-month following Cre recombination, adenoma formation was observed in a small proportion of Krt15△Trp53 mice. Though, Trp53 loss in Krt15+ cells severely perturbed the small intestinal morphology in every mouse studied. Increased crypt length and villi width was observed in Krt15△Trp53 vs control mice without any changes in cell proliferation. We also observed an increased number of Tuft cells and goblet cells in the villi of experimental mice. In the crypt, higher number of Paneth cells and aberrant presence of goblet cells were noted in Krt15△Trp53mice. Interestingly, we also observed crypt cells expressing goblet and Paneth cell markers and decreased Notch pathway activation suggesting dysregulation of secretory cell fate. Krt15△Trp53 mice display higher number of fibroblasts in the villi and the submucosa, as well as thickening of the muscularis layer. Interestingly, similar observations (accumulation of secretory cells and fibrosis) have been reported in IBD patients, supporting the possible role of Krt15+ cells in CAC. Furthermore, crypts isolated from Krt15△Trp53 mice rapidly die when seeded as organoids vs crypts from control mice, suggesting that the alterations observed in vivo in Paneth cells might interfere with the stem cell niche and therefore reduce self-renewal of Krt15+ cells. Conclusions Trp53 loss specifically in Krt15+ cells impaired cell fate decision, induced secretory cell hyperplasia, affected self-renewal ability, and initiated adenoma formation supporting the possible role of Krt15+ cells in gut inflammation and cancer. Funding Agencies Canada Research Chair, Cancer Research Society, CFI

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