A Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation

E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease. To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen. These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone

Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition

Induction of epithelial-to-mesenchymal transition (EMT) in cancer stem cells (CSCs) can occur as the result of embryonic pathway signaling. Activation of Hedgehog (Hh), Wnt, Notch, or transforming growth factor-β leads to the upregulation of a group of transcriptional factors that drive EMT. This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. CSCs and the EMT process are currently being investigated for the role they play in driving metastatic tumor formation in breast cancer. Both are very closely associated with embryonic signaling pathways that stimulate self-renewal properties of CSCs and EMT-inducing transcription factors. Understanding these mechanisms and embryonic signaling pathways may lead to new opportunities for developing therapeutic agents to help prevent metastasis in breast cancer. In this review, we examine embryonic signaling pathways, CSCs, and factors affecting EMT

Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs

PPARβ as a molecular link between Wnt and Hedgehog signaling pathways in intestinal development and repair

Summary The small intestine is of prime interest with respect to its pattern of development, which depends on cell proliferation, growth, differentiation, migration and apoptosis. The Wnt, Hedgehog and BMP signaling pathways are deeply involved in its development and, at the adult stage, in maintaining a small crypt stem cell population. We first demonstrate that, in normal small intestine development, PPARβ is the molecular bridge that allows Wnt to modulate the expression of Indian hedgehog. The latter is crucial for proper epithelial cell differentiation, especially for the differentiation of Paneth cell precursors into mature cells that are important for the establishment of the intestinal anti-microbial barrier. Importantly, our results also suggest that this novel link between Wnt and hedgehog signaling via PPARβ, not only operates in normal development but also in tumorigenesis, as observed in human patients with familial adenomatous polyposis and in the ApcMin/+ mouse model. Finally our findings suggest an unsuspected involvement of the Paneth cells in small intestinal tumor development. Secondly, we show that PPARβ is an important modulator of BMP signaling activity which is mainly pro-apoptotic. Particularly, PPARβ activation is able to inhibit the apoptotic process induced by γ-irradiation of cultured enterocytes. This effect on cell survival is accompanied by a strong reduction of BMP signaling activity. Importantly, these observation in vitro are correlated with the recovery defect observed in vivo in PPARβ null mice after γ-irradiation. Finally, we highlight the potential involvement of BMP signaling activity in the PPARβ dependant growth of the intestinal adenomas. Altogether, our work emphasizes the importance of PPARβ in intestinal development and homeostasis. As a nuclear receptor, PPARβ might therefore be an extremely useful target for drugs, either agonists or antagonists.  Résumé Le petit intestin est d'un intérêt majeur pour la compréhension des phénomènes de prolifération cellulaire, de différenciation, de migration et d'apoptose. Les voies de signalisation Wnt et Hedgehog sont fortement impliquées dans le développement intestinal et, à l'âge adulte, dans l'homéostasie des cellules souche résidant dans les cryptes. Dans ce travail, nous démontrons dans un premier temps que PPARβ est le lien moléculaire qui permet à la voie de signalisation Wnt de moduler l'expression de Ihh au niveau de l'épithélium intestinal des souris adultes. Nos expériences révèlent en effet que Ihh est indispensable à la différenciation des cellules de l'épithélium intestinal et plus précisément à la différenciation des précurseurs des cellules de Paneth en cellules matures indispensables à la protection anti-microbienne du petit intestin. De façon intéressante, nos résultats suggèrent aussi que ce nouveau lien entre les voies de signalisation Wnt et Hedgehog via PPARβ intervient non seulement dans le développement normal mais aussi dans le développement des tumeurs intestinales comme l'illustrent nos observations chez les patients atteint de Polypose Adenomateuse Familiale et chez le modèle murin ApcMin/+. Finalement, nos travaux suggèrent un rôle inédit des cellules de Paneth dans la croissance des adénomes intestinaux. Dans un second temps, nous démontrons que PPARβ est un important régulateur de l'activité de la voie de signalisation BMP dont la fonction au niveau de l'épithélium intestinal est principalement pro-apoptotique. Plus précisément, l'activation de PPARβ inhibe le processus d'apoptose des entérocytes en culture induit par un rayonnement γ. Cet effet sur la survie cellulaire est accompagné par une forte réduction de l'activité de la voie de signalisation BMP. De plus, ces observations in vitro sont a mettre en parallèle avec le défaut de régénération observé in vivo chez les souris mutantes pour PPARβ après exposition à un rayonnement γ. Finalement, nous soulignons la possibilité d'une implication de la voie de signalisation BMP dans la croissance des adénomes intestinaux dépendante de PPARβ. En conclusion, notre travail met en évidence l'importance de PPARβ dans le développement intestinal et dans son homéostasie ce qui nous permet d'envisager une issue intéressante pour l'utilisation d'antagonistes ou d'agonistes de ce récepteur nucléaire

PPARs: lipid sensors that regulate cell differentiation processes

We considered the risk of subsequent invasive breast cancer in a population-based series of 579 carcinomas in situ (CIS) of the breast (482 ductal, 88 lobular) registered between 1977 and 2002 in the Swiss Canton of Vaud. A total of 55 cases of invasive breast cancer were observed vs. 12.3 expected, corresponding to a standardized incidence ratio (SIR) of 4.5 (95% confidence interval [CI], 3.4-5.8). The SIR was 4.6 after ductal and 4.2 after lobular CIS, was similar with passing time since CIS diagnosis, but was higher (SIR = 5.5) for women aged &lt;55 years. At 20 years following CIS, the cumulative risk of invasive breast cancer was 26%, similar for lobular and for ductal CIS. The incidence of invasive breast cancer following CIS showed no consistent pattern of trends with age, all rates in subsequent age groups ranging between 10 and 18 in 1,000. This is compatible with the occurrence of a single mutational event in a population of susceptible women. [Ed.]]]> Breast Neoplasms ; Carcinoma in Situ ; Carcinoma, Ductal, Breast ; Carcinoma, Lobular oai:serval.unil.ch:BIB_03A0161C9A23 2022-02-19T02:12:46Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_03A0161C9A23 L'EXECUTION TESTAMENTAIRE ETENDUE PHAM, Kim Lan Université de Lausanne, Faculté de droit, des sciences criminelles et d'administration publique info:eu-repo/semantics/doctoralThesis phdthesis 2019 fre oai:serval.unil.ch:BIB_04199AE39171 2022-02-19T02:12:48Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_04199AE39171 Functional sphere profiling reveals the complexity of neuroblastoma tumor-initiating cell model. info:eu-repo/semantics/altIdentifier/pmid/22028624 Coulon, A. Flahaut, M. Mühlethaler-Mottet, A. Meier, R. Liberman, J. Balmas-Bourloud, K. Nardou, K. Yan, P. Tercier, S. Joseph, J.M. Sommer, L. Gross, N. info:eu-repo/semantics/article article 2011 Neoplasia, vol. 13, no. 10, pp. 991-1004 info:eu-repo/semantics/altIdentifier/eissn/1476-5586 urn:issn:1476-5586 <![CDATA[Neuroblastoma (NB) is a neural crest-derived childhood tumor characterized by a remarkable phenotypic diversity, ranging from spontaneous regression to fatal metastatic disease. Although the cancer stem cell (CSC) model provides a trail to characterize the cells responsible for tumor onset, the NB tumor-initiating cell (TIC) has not been identified. In this study, the relevance of the CSC model in NB was investigated by taking advantage of typical functional stem cell characteristics. A predictive association was established between self-renewal, as assessed by serial sphere formation, and clinical aggressiveness in primary tumors. Moreover, cell subsets gradually selected during serial sphere culture harbored increased in vivo tumorigenicity, only highlighted in an orthotopic microenvironment. A microarray time course analysis of serial spheres passages from metastatic cells allowed us to specifically "profile" the NB stem cell-like phenotype and to identify CD133, ABC transporter, and WNT and NOTCH genes as spheres markers. On the basis of combined sphere markers expression, at least two distinct tumorigenic cell subpopulations were identified, also shown to preexist in primary NB. However, sphere markers-mediated cell sorting of parental tumor failed to recapitulate the TIC phenotype in the orthotopic model, highlighting the complexity of the CSC model. Our data support the NB stem-like cells as a dynamic and heterogeneous cell population strongly dependent on microenvironmental signals and add novel candidate genes as potential therapeutic targets in the control of high-risk NB