Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells

Francescangeli, Federica; Patrizii, Michele; Signore, Michele; Federici, Giulia; Franco, Simone Di; Pagliuca, Alfredo; Baiocchi, Marta; Biffoni, Mauro; Ricci–Vitiani, Lucia; Todaro, Matilde; Maria, Ruggero De; Zeuner, Ann

doi:10.1002/stem.1163

Cited by 53 publications

(44 citation statements)

References 32 publications

(37 reference statements)

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“…In other words vincristine most likely affected viability of differentiated tumor cells sparing LMS-stem-like cells, while the combination treatment was effective against both stem-like and differentiated cells. This is in line with recent data from our group showing that in different solid tumors chemotherapy spares quiescent rather than proliferating cancer stem-like cells [39], [40]. However, another interpretation might be that vincristine could determine the selection of cells with increased proliferative potential.…”

Section: Discussionsupporting

confidence: 91%

EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential

et al. 2012

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BackgroundTumor cells with stem-like phenotype and properties, known as cancer stem cells (CSC), have been identified in most solid tumors and are presumed to be responsible for driving tumor initiation, chemoresistance, relapse, or metastasis. A subpopulation of cells with increased stem-like potential has also been identified within sarcomas. These cells are endowed with increased tumorigenic potential, chemoresistance, expression of embryonic markers, and side population(SP) phenotype. Leiomyosarcomas (LMS) are soft tissue sarcomas presumably arising from undifferentiated cells of mesenchymal origin, the Mesenchymal Stem Cells (MSC). Frequent recurrence of LMS and chemoresistance of relapsed patients may likely result from the failure to target CSC. Therefore, therapeutic cues coming from the cancer stem cell (CSC) field may drastically improve patient outcome.Methodology/Principal FindingsWe expanded LMS stem-like cells from patient samples in vitro and examined the possibility to counteract LMS malignancy through a stem-like cell effective approach. LMS stem-like cells were in vitro expanded both as “tumor spheres” and as “monolayers” in Mesenchymal Stem Cell (MSC) conditions. LMS stem-like cells displayed MSC phenotype, higher SP fraction, and increased drug-extrusion, extended proliferation potential, self-renewal, and multiple differentiation ability. They were chemoresistant, highly tumorigenic, and faithfully reproduced the patient tumor in mice. Such cells displayed activation of EGFR/AKT/MAPK pathways, suggesting a possibility in overcoming their chemoresistance through EGFR blockade. IRESSA plus Vincristine treatment determined pathway inactivation, impairment of SP phenotype, high cytotoxicity in vitro and strong antitumor activity in stem-like cell-generated patient-like xenografts, targeting both stem-like and differentiated cells.Conclusions/SignificanceEGFR blockade combined with vincristine determines stem-like cell effective antitumor activity in vitro and in vivo against LMS, thus providing a potential therapy for LMS patients.

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Section: Discussionsupporting

confidence: 91%

EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential

et al. 2012

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“…Previous studies by our and other laboratories reported that multicellular spheroid suspensions enriched in CSCs could be obtained by the selective culture of cells extracted from colorectal tumor specimens in serum-free media [6,[15][16][17][18]. We improved previous culture methods through supplementation with factors identified by Sato et al (nicotinamide and Y-27632), which are also essential for the in vitro growth of normal intestinal stem cells [19], reaching approximately 40% of success in the generation of CSC cultures from tumor specimens (supplemental online Table 1).…”

Section: A Protocol For the Isolation Profiling And Functional Analmentioning

confidence: 99%

“…The cell suspension was then filtered through a 100-mm nylon mesh, and washed by 2 further centrifugation steps in DMEM. Finally, pellets containing cells, cell clusters, and tissue fragments were resuspended in CSC medium [6] supplemented with 10 mM nicotinamide, 1 mM Y-27632 (both from Sigma-Aldrich, St. Louis, MO, http://www.sigmaaldrich.com), 20 ng/ml human EGF and 10 ng/ml human basic fibroblast growth factor (both from PeproTech, London, U.K., https://www.peprotech.com). The resulting suspension was plated in ultra-low attachment tissue culture flasks (Corning Costar, Cambridge, MA, https://www.…”

Section: Csc Isolation and Culturementioning

confidence: 99%

Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance

Angelis

Zeuner

Policicchio

et al. 2016

Stem Cells Translational Medicine

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Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.

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“…Our studies further show that this population is enriched upon nutritional deprivation, low dose chemotherapy as well as presence of hypoxia 21, 25, 26 . We and others have shown that CD133+ population are generally slow-cycling or quiescent 2, 6, 36 . This indicates that the cell cycle plays an active role in maintenance of this population in a quiescent and slow cycling state.…”

Section: Introductionmentioning

confidence: 69%

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Sharma

Gnamlin

Durden

et al. 2019

Preprint

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Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence.This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a "fail-safe" mechanism to prevent expansion of malignant cells to prevent further injury.Upon removal of the "stress" conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-noncoding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse.In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors. 25, 26 . We and others have shown that CD133+ population are generally slow-cycling or quiescent 2, 6, 36 . This indicates that the cell cycle plays an active role in maintenance of this population in a quiescent and slow cycling state.Growth Arrest Specific 5 or GAS5, is a long non-coding RNA regulates cell cycle in a number of mammalian systems including several cancers 7, 15, 16, 23 . It also mediates cell proliferation by regulating CDK6 activity 17 . Studies have also shown that GAS5 forms a positive feedback network with a number of genes involved in self-renewal like Sox2/Oct4, making this long noncoding RNA (LncRNA) a critical player in induction and maintenance of the "stemness" state in a tumor 34 . GAS5 is further involved in regulation of human embryonic stem cell self-renewal by maintaining NODAL signaling 38 . Mechanistically, the effect of GAS5 on cell cycle is regulated by its interaction with the glucocorticoid receptor (GR) 11 . GRs are nuclear receptor proteins that control cell proliferation via their effect on cell cycle 30 . GAS5 interacts with the activated GR

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Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells

Cited by 53 publications

References 32 publications

EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential

EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential

Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

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