Neoexpression of a functional primary cilium in colorectal cancer cells

Sénicourt, Blanche; Boudjadi, Salah; Carrier, Julie; Beaulieu, Jean‐François

doi:10.1016/j.heliyon.2016.e00109

Cited by 8 publications

(15 citation statements)

References 63 publications

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“…Rare reports from detailed electron microscopy (EM) observations of mouse intestine have clearly established that the terminally differentiated intestinal epithelial cells of the villus, which are quiescent, do not generate primary cilia [ 27 ]. The lack of primary cilia in the normal intestinal epithelium was further confirmed by various reports [ 26 , 28 , 29 , 30 ] albeit their ubiquitous presence in the stroma and muscle cells of the intestinal wall [ 26 , 28 , 29 , 31 ].…”

Section: Introductionsupporting

confidence: 59%

“…These latter cells are highly proliferative and undifferentiated and are replenished by a robust stem cell population residing in the crypt [ 23 ]. While the primary cilium has been generally reported in quiescent cells [ 24 ], since the basal body from which the cilium grows needs to be converted into the centrosome required for the mitotic spindle in proliferative cells [ 25 ], it seems in fact that only cells directly under the mitotic process cannot grow a primary cilium [ 1 , 4 , 26 ]. Nevertheless, in the intestinal epithelium, the transit-amplifying crypt cells and the primordial stem cells from which they are derived appear not to be able to assemble primary cilia.…”

Section: Introductionmentioning

confidence: 99%

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Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt

Sénicourt

Cloutier

Basora

et al. 2023

Cells

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Primary cilia are sensory antennae located at the cell surface which mediate a variety of extracellular signals involved in development, tissue homeostasis, stem cells and cancer. Primary cilia are found in an extensive array of vertebrae cells but can only be generated when cells become quiescent. The small intestinal epithelium is a rapidly self-renewing tissue organized into a functional unit called the crypt–villus axis, containing progenitor and differentiated cells, respectively. Terminally differentiated villus cells are notoriously devoid of primary cilia. We sought to determine if intestinal crypts contain a quiescent cell population that could be identified by the presence of primary cilia. Here we show that primary cilia are detected in a subset of cells located deep in the crypts slightly above a Paneth cell population. Using a normal epithelial proliferative crypt cell model, we show that primary cilia assembly and activity correlate with a quiescent state. These results provide further evidence for the existence of a quiescent cell population in the human small intestine and suggest the potential for new modes of regulation in stem cell dynamics.

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Section: Introductionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt

Sénicourt

Cloutier

Basora

et al. 2023

Cells

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“…Primary (HCT 116, SW480) and metastatic (SW620) human CC cell lines were grown in DMEM supplemented with 10% FBS (GIBCO® Life Technology, Monza, Italy) and antibiotics. These cellular lines were reported to express detectable levels of SMO and GLI1 (Sun et al, 2013 ; Sénicourt et al, 2016 ; Wang et al, 2017 ). MeT5A cells, a human mesothelium non-tumorigenic cell line were grown in M199 supplemented with 10% FBS (GIBCO® Life Technology, Monza, Italy) and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

et al. 2018

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HIGHLIGHTS Preliminary results of this work were presented at the 2016 Academic Surgical Congress, Jacksonville (FL), February 2–4 2016 (Original title: Selective Smo-Inhibition Interferes With Cellular Energetic Metabolism In Colorectal Cancer)This study was funded by “Sapienza—University of Rome” (Funds for young researchers) and “AIRC” (Italian Association for Cancer Research)Hedgehog inhibitor was kindly provided by Genentech, Inc.®.Colon Cancer (CC) is the fourth most frequently diagnosed tumor and the second leading cause of death in the USA. Abnormalities of Hedgehog pathway have been demonstrated in several types of human cancers, however the role of Hedgehog (Hh) in CC remain controversial. In this study, we analyzed the association between increased mRNA expression of GLI1 and GLI2, two Hh target genes, and CC survival and recurrence by gene expression microarray from a cohort of 382 CC patients. We found that patients with increased expression of GLI1 showed a statistically significant reduction in survival. In order to demonstrate a causal role of Hh pathway activation in the pathogenesis of CC, we treated HCT 116, SW480 and SW620 CC cells lines with GDC-0449, a pharmacological inhibitor of Smoothened (SMO). Treatment with GDC-0449 markedly reduced expression of Hh target genes GLI1, PTCH1, HIP1, MUC5AC, thus indicating that this pathway is constitutively active in CC cell lines. Moreover, GDC-0449 partially reduced cell proliferation, which was associated with upregulation of p21 and downregulation of CycD1. Finally, treatment with the same drug reduced migration and three-dimensional invasion, which were associated with downregulation of Snail1, the EMT master gene, and with induction of the epithelial markers Cytokeratin-18 and E-cadherin. These results were confirmed by SMO genetic silencing. Notably, treatment with 5E1, a Sonic Hedgehog-specific mAb, markedly reduced the expression of Hedgehog target genes, as well as inhibited cell proliferation and mediated reversion toward an epithelial phenotype. This suggests the existence of a Hedgehog autocrine signaling loop affecting cell plasticity and fostering cell proliferation and migration/invasion in CC cell lines. These discoveries encourage future investigations to better characterize the role of Hedgehog in cellular plasticity and invasion during the different steps of CC pathogenesis.

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“…PC is lost in a group of developmental genetic disorders, collectively known as ciliopathies, and in a variety of human neoplasms [ 5 ], leading to the hypothesis that PC is a tumor-suppressor organelle [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. However, different cancers retain PC, such as basal cell carcinomas (BCC), pleomorphic adenomas, neuroblastoma, colorectal tumors, craniopharyngioma, a subset of medulloblastoma and gastrointestinal stromal tumors [ 13 , 14 , 15 , 16 , 17 , 18 ], supporting the recent hypothesis that PC has tissue- and cancer-specific roles.…”

Section: Introductionmentioning

confidence: 94%

Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology

Barbarino

Bottaro

Spagnoletti

et al. 2022

Cancers

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The primary cilium (PC) is a sensory organelle present on the cell surface, modulating the activity of many pathways. Dysfunctions in the PC lead to different pathologic conditions including cancer. Hedgehog signaling (Hh) is regulated by PC and the loss of its control has been observed in many cancers, including mesothelioma. Malignant pleural mesothelioma (MPM) is a fatal cancer of the pleural membranes with poor therapeutic options. Recently, overexpression of the Hh transcriptional activator GL1 has been demonstrated to be associated with poor overall survival (OS) in MPM. However, unlike other cancers, the response to G-protein-coupled receptor smoothened (SMO)/Hh inhibitors is poor, mainly attributable to the lack of markers for patient stratification. For all these reasons, and in particular for the role of PC in the regulation of Hh, we investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with the activation of the Hh pathway, providing uncovered evidence of a PC-independent regulation of the Hh signaling in MPM. Our study contributes to the understanding MPM heterogeneity, thus helping to identify patients who might benefit from Hh inhibitors.

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Neoexpression of a functional primary cilium in colorectal cancer cells

Cited by 8 publications

References 63 publications

Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt

Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt

SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology

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