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Background Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinical significance in GC patients. Methods Using GC cell lines and patient-derived xenografts, we evaluated CD44+ and CD44v3+ GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues. Results CD44v3+ cells, which represented a subpopulation of CD44+ cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+ CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3– CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+ cells detected in the primary tumours of GC patients were associated with a worse prognosis. Conclusion CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies.

Effect of verapamil treatment in combination with dose-dependent chemotherapies on gastric cancer cell lines viability.

Detection of cells expressing CD44 and ALDH activity in gastric tumorspheres in vitro.

Detection of ALDH+ population with SP protocol and with ALDEFLUOR protocol.

Supplementary experimental procedures,figure legends and references

Annexin II expression is not enriched in cancer stem cell populations.

Description of additional methods and procedures used in the study.

Subpopulations of cancer stem–like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference–mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDHhigh cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDHhigh CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618–28. ©2016 AACR.

Legend for Supplemental Figures S1-S6.

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral and non-viral etiologies. Immune checkpoint blockade primarily benefits patients with viral HCC. Expansion of suppressive myeloid cells is a hallmark of chronic inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance in the steatohepatitis setting. Here, we present a high resolution atlas of hepatic innate immune cells from patients with HCC that unravels a steatohepatitis contexture characterized by the emergence of high entropy myeloid cell states and myeloid-biased NK cell differentiation. We identify a discrete population of tumor-infiltrating myeloid cells, predominant in the steatohepatitis setting, that expresses a variety of myeloid lineage-affiliated genes, including granulocyte, macrophage and dendritic cell features, and can be identified in HCC tumors based on selective dual expression ofTREM1andCD163. Functional characterization reveals that TREM1+CD163+myeloid cells highly express TGFβ and IL-13RA, localize to HCC fibrotic lesions, and potently suppress T cell effector functionsex vivo, a function further potentiated by TREM1 engagement. We refer to this population as TREM1+CD163+regulatory myeloid cells (TREM1+CD163+Mreg). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1+CD163+Mregincreases in advanced stages, associates with poor prognosis, and therapeutic resistance to PD-1 blockade. Our data support myeloid subset-targeted immunotherapies to treat HCC and identify TREM1 as a therapeutic target.HIGHLIGHTSAtlas of hepatic innate immune cells (100,000 transcriptomes) from patients with HCCCore signatures to identify, discriminate and localize innate lymphoid and myeloid cellsA population of TREM1+CD163+myeloid cells, referred to as TREM1+CD163+Mreg, expands in steatohepatitis HCCTREM1+CD163+Mregexpress granulocyte- and macrophage/dendritic cell-lineage genesTREM1+CD163+Mregpotently suppress T cell effector functions, which is potentiated by TREM1 engagement by cognate ligandsTREM1+CD163+Mregproduce high levels of TGFβ and populate fibrotic lesionsThe density of TREM1+CD163+Mregincreases in advanced HCC and associate with poor patient survivalThe density of TREM1+CD163+Mregassociates with resistance to immune checkpoint blockade in other solid tumors

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial&ndash, mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZ silencing reduced ZEB1 expression and EMT phenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis.

The hospital-community interface represents a real challenge in the care of elderly people. A lack of coordination and communication is the main obstacle to ensuring the fluidity of this pathway. On a definite territory, a new hospital-community liaison sheet was developed as the result of a collaborative approach and then evaluated. This simple, useful and effective cross-professional tool, is the first step towards improving communication between these two universes.

Cancer stem cells (CSCs) present chemo-resistance mechanisms contributing to tumour maintenance and recurrence, making their targeting of utmost importance in gastric cancer (GC) therapy. The Hippo pathway has been implicated in gastric CSC properties and was shown to be regulated by leukaemia inhibitory factor receptor (LIFR) and its ligand LIF in breast cancer. This study aimed to determine LIF&rsquo, s effect on CSC properties in GC cell lines and patient-derived xenograft (PDX) cells, which remains unexplored. LIF&rsquo, s treatment effect on CSC markers expression and tumoursphere formation was evaluated. The Hippo kinase inhibitor XMU-MP-1 and/or the JAK1 inhibitor Ruxolitinib were used to determine Hippo and canonical JAK/STAT pathway involvement in gastric CSCs&rsquo, response to LIF. Results indicate that LIF decreased tumorigenic and chemo-resistant CSCs, in both GC cell lines and PDX cells. In addition, LIF increased activation of LATS1/2 Hippo kinases, thereby decreasing downstream YAP/TAZ nuclear accumulation and TEAD transcriptional activity. LIF&rsquo, s anti-CSC effect was reversed by XMU-MP-1 but not by Ruxolitinib treatment, highlighting the opposite effects of these two pathways downstream LIFR. In conclusion, LIF displays anti-CSC properties in GC, through Hippo kinases activation, and could in fine constitute a new CSCs-targeting strategy to help decrease relapse cases and bad prognosis in GC.

Highlights • Secretion of progastrin is a signature event of early malignant transformation in the colon. • In the healthy epithelium, progastrin is produced by a subset of enteroendocrine cells expressing both Bmi1 and Prox1. • LGR5-high intestinal stem cells are a primary source of progastrin production in early mouse and human intestinal adenomas., Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice, gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells&rsquo, phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies.

Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation-44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T-TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration-approved drug preventing Y/T-TEAD interaction, on gastric CSC tumorigenic properties. Y/T-TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient-derived GC and cell lines. Verteporfin effects on Y/T-TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patientderived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T-TEAD molecular signature was enriched in CD44+ patientderived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T-TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere-forming CD44+/aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T-TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ-TEAD activity could be a promising CSC-based strategy for the treatment of GC. French Institute for Central America/[]/IFAC/Francia Institut National du Cancer/[2014-152]/INCA/Francia Universidad de Costa Rica/[]/UCR/Costa Rica Ministerio de Ciencia, Innovación, Tecnología y Telecomunicaciones/[]/MICITT/Costa Rica Ligue Nationale Contre le Cancer/[]//Francia Les Sites de Recherche Intégrée sur le Cancer/[R16055GG]/SIRIC BRIO/Francia UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA) UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Medicina

International audience; Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.

Resume Le processus metastatique est defini comme « une dissemination de cellules neoplasiques dans un site secondaire non contigu et distant, au sein duquel ces cellules proliferent pour former une masse extravasculaire de cellules incompletement differenciees ». La majorite des deces imputables aux cancers solides est la consequence de l’apparition et du developpement de metastases disseminees qui sont responsables a terme de la dysfonction d’organes vitaux. Dans cette revue un certains de nombre de points, soit recemment decouverts soit sujets a controverse, sont abordes. En effet il sera discute de la transition epithelio-mesenchymateuse (EMT), des cellules tumorales circulantes, de la dormance tumorale, de la colonisation dans un organe distant et enfin des cellules souches cancereuses.

Introduction Le carboxymaltose ferrique (CMF) est une des formes injectables du fer. La posologie est calculee en fonction du poids et du taux d’hemoglobine, et la dose totale doit etre administree en 2 injections a une semaine d’intervalle si elle est superieure a 1 g. Il est indique dans l’anemie par carence martiale, qui est une affection courante chez l’insuffisant cardiaque (IC) associe ou non a une anemie. Le CMF reduit les symptomes, en particulier la dyspnee, et les hospitalisations tant en nombre qu’en frequence. Les recommandations de l’European Society of Cardiology (ESC) preconisent du CMF lorsqu’une ferritine serique est inferieure a 100 μg/L ou entre 100 et 299 μg/L avec un coefficient de saturation de la transferrine inferieur a 20 %. La consommation de CMF ayant fortement augmente ces dernieres annees, avec un cout non negligeable, l’AP–HP a decide de creer un groupe de travail afin d’editer de nouvelles recommandations. Ce travail a pour but de realiser une evaluation des pratiques professionnelles dans les services de cardiologie de notre hopital. Materiels et methode Une etude retrospective a ete menee du 1er janvier a fin juillet 2018 sur l’ensemble des prescriptions de CMF dans les 6 unites de cardiologie. Les donnees suivantes ont ete recoltees a partir des dossiers medicaux informatises : sexe, poids, hemoglobine, presence d’une IC, bilan martial, chirurgie, posologie et dose administree de CMF. Les patients sans dossier medical informatise ont ete exclus. Resultats et discussion Au total 193 patients, tous presentant une anemie, ont recu du CMF(sex-ratio :1,56) : 92 patients IC, 38 une carence martiale, 45 en post-operatoire, 18 sans indications. Concernant les patients IC 57 avaient une carence martiale et 29 aucun bilan ferrique prealablement realises (31,5 %). La principale indication des patients non IC etait la chirurgie (44,6 %). Concernant la prescription de CMF 43,5 % des patients ont recu la dose totale et ce taux passe a 15,8 % pour les patients devant recevoir une dose superieure a 1 g. Les patients non IC mais ayant eu une chirurgie ont le plus haut taux d’administration de seconde dose avec 35,5 % (n = 22/45). Conclusion Cette etude a mis en evidence un important mesusage du CMF. Le complement d’administration pour les doses de plus de 1 g n’est pas souvent realise. Diverses causes sont possibles : la sortie precoce du patient, une remontee rapide de l’hemoglobine. Aussi 9 % des patients ont recu du CMF sans indication et 31,5 % des patients IC n’ont pas eu de bilan martial, ce qui ne suit pas les recommandations de l’ESC. A noter nombreux sont les patients qui ont ete operes pour lequel on peut penser que des transfusions ont ete realisees. Or une injection de CMF pourrait conduire a une surcharge en fer. Ces differents points seront a rediscuter avec les prescripteurs au cours du groupe de travail.

MicroRNAs are key factors in the regulation of gene expression and their deregulation has been directly linked to various pathologies such as cancer. The use of small molecules to tackle the overexpression of oncogenic miRNAs has proved its efficacy and holds the promise for therapeutic applications. Here we describe the screening of a 640-compound library and the identification of polyamine derivatives interfering with in vitro Dicer-mediated processing of the oncogenic miR-372 precursor (pre-miR-372). The most active inhibitor is a spermine-amidine conjugate that binds to the pre-miR-372 with a KD of 0.15 µM, and inhibits its in vitro processing with a IC50 of 1.06 µM. The inhibition of miR-372 biogenesis was confirmed in gastric cancer cells overexpressing miR-372 and a specific inhibition of proliferation through de-repression of the tumor suppressor LATS2 protein, a miR-372 target, was observed. This compound modifies the expression of a small set of miRNAs and its selective biological activity has been confirmed in patient-derived ex vivo cultures of gastric carcinoma. Polyamine derivatives are promising starting materials for future studies about the inhibition of oncogenic miRNAs and, to the best of our knowledge, this is the first report about the application of functionalized polyamines as miRNAs interfering agents.

Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of &gt, 4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC.

International audience; Gastric cancer is the third leading cause of cancer-related deaths worldwide and has still a poor prognosis. Therefore, new therapeutic strategies are needed: among them, targeting cancer stem cells (CSCs) could offer new opportunities. The aim of our study was to evaluate the anti-tumoural effect of metformin on gastric cancer in vitro and in vivo and especially, to determine whether this molecule could target the gastric CSCs. Metformin effects were evaluated on the proliferation and tumourigenic properties of the gastric CSCs from patient-derived primary tumour xenografts (PDXs) and cancer cell lines (MKN45, AGS and MKN74) in vitro in conventional 2 dimensional (2D) and in 3 dimensional (3D) culture systems, in which only CSCs are able to form tumourspheres and in mouse xenograft models in vivo. Metformin induced a cell cycle arrest, which decreased cell proliferation in the 2D cultures. In a 3D culture system, metformin decreased the number of tumourspheres, revealing its capacity to target the CSCs. This effect was confirmed by the study of the expression of CSC markers (CD44 and Sox2) and differentiation markers (Kruppel-like factor 4 and MUC5AC), which were decreased or increased in response to metformin, respectively. Finally, in vivo treatment of PDXs with metformin led to a tumour growth delay and decreased the self-renewal ability of the CSCs. These results suggest that the use of metformin could represent an efficient strategy to inhibit tumour growth by targeting gastric CSCs.

The hospital-community interface represents a real challenge in the care of elderly people. A lack of coordination and communication is the main obstacle to ensuring the fluidity of this pathway. On a definite territory, a new hospital-community liaison sheet was developed as the result of a collaborative approach and then evaluated. This simple, useful and effective cross-professional tool, is the first step towards improving communication between these two universes.

Introduction La survenue de neutropenies febriles (NF) avec le risque de complications infectieuses est un effet indesirable (EI) majeur des anticancereux. Les facteurs de croissance granulocytaire (G-CSF) permettent entre autre de reduire le nombre d’episodes de neutropenie et la consommation d’antibiotiques. Bien qu’aucune recommandation officielle n’existe en France, plusieurs societes savantes (National Comprehensive Cancer Network, et l‘European Organisation for Research and Treatment of Cancer, Journal of Pharmacovigilance) recommandent une utilisation en curatif, et en prevention primaire (en fonction du risque de NF) ou secondaire. L’objectif est d’evaluer les pratiques de prescription du G-CSF chez les patients traites dans un service de medecine interne (MI), en les confrontant aux recommandations internationales (RI). Materiels et methode Une etude retrospective a ete menee sur les patients ayant recu une cure de chimiotherapie pour un cancer solide au cours d’une hospitalisation en MI entre janvier 2015 et fevrier 2018. Les donnees suivantes ont ete recueillies via le dossier informatique : âge, sexe, protocole de chimiotherapie et type de cancer (pour le calcul du risque de NF), molecule de G-CSF administree, indication, duree de traitement et delai moyen d’instauration apres le debut de la cure, et les EI inattendus. Les prescriptions de G-CSF ont ete confrontees aux RI pour savoir si elles etaient conformes en fonction du risque de NF pour la prevention primaire. Resultats et discussion Quarante-huit patients ont recu une cure de chimiotherapie (ratio H/F = 0,66), avec un âge moyen de 61,7 ans (36–90). On compte 23 cancers pulmonaires, 9 seins, 7 ovaires-uterus et 9 autres (colon,…). Sur les 68 cures, il y a eu 28 prescriptions de G-CSF : 22 preventions primaires, 4 preventions secondaires et 2 curatives. Concernant les 28 cures sous G-CSF, les molecules utilisees etaient 12 pegfilgastrim, 15 filgastrim et 1 lenograstim pour une administration a domicile. Le pegfilgastrim a ete prescrit pour 1 journee alors que le filgastrim pendant en moyenne 3,5 jours (1–10), avec un delai moyen d’instauration de 3,4 et 5,9 jours respectivement. Seules 61 des 68 cures realisees ont ete analysees car 7 d’entre elles n’ont pas pu etre classifiees selon les RI. Sur les 61 cures, 45 etaient justifiees selon les RI : 21 avec du G-CSF, 24 sans. Pour les 16 cures qui n’ont pas suivi les RI : 12 patients auraient du en recevoir et n’en n’ont pas eu et 4 en ont recu alors qu’ils n’en necessitaient pas. On a observe 7 EI inattendus parmi les 25 cures sous G-CSF (4 neutropenies ; et 3 infections dont 1 NF). Un seul des 4 patients qui a eu du G-CSF a l’encontre des RI, a fait une neutropenie. On a note 3 EI (dont 1 neutropenie) sur les 36 cures sans GCSF, tous ont eu lieu chez des patients qui n’avaient pas d’indication a en recevoir. Conclusion En MI plus de 70 % prescriptions de G-CSF suivent les RI et 78 % de celles-ci sont indiquees en prevention primaire. Bien qu’une tendance a la sous prescription existe, les patients n’ont pas fait plus d’evenements inattendus.

Metastatic process is described as a "dissemination of neoplastic cells in a distant secondary site, in which cells proliferate to develop a mass of cells partially differentiated". The vast majority of death in solid cancers is the consequence of metastasis development which lead to vital organ dysfunction. In the present review, either recent discoveries or controversial subjects associated with metastasis process will be discussed. Indeed epithelia-mesenchymal transition (EMT), circulating tumor cells, tumor dormancy, colonization in distant organ and cancer stem cells are tackled.

Subpopulations of cancer stem–like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference–mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDHhigh cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDHhigh CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618–28. ©2016 AACR.

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-trans-retinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.

Background The association between area characteristics and birth outcomes is modified by race. Whether such associations vary according to social class indicators beyond race has not been assessed. Methods This study evaluated effect modification by maternal birthplace and education of the relationship between neighbourhood characteristics and birth outcomes of newborns from 1999–2003 in the province of Québec, Canada (N = 353,120 births). Areas (N = 143) were defined as administrative local health service delivery districts. Multi-level logistic regression was used to model the association between three area characteristics (median household income, immigrant density and income inequality) and the two outcomes preterm birth (PTB) and small-for-gestational age (SGA) birth. Effect modification by social class indicators was evaluated in analyses stratified according to maternal birthplace and education. Results Relative to the lowest tertile, high median household income was associated with SGA birth among Canadian-born mothers (odds ratio (OR) 1.13, 95% confidence interval (CI) 1.06, 1.20) and mothers with high school education or less (OR 1.13, 95% CI 1.02, 1.24). Associations between median household income and PTB were weaker. Relative to the highest tertile, low immigrant density was associated with a lower odds of PTB among foreign-born mothers (OR 0.79, 95% CI 0.63, 1.00) but a higher odds of PTB among Canadian-born mothers (OR 1.14, 95% CI 1.07, 1.21). Associations with income inequality were weak or absent. Conclusion The association between area factors and birth outcomes is modified by maternal birthplace and education. Studies have found that race interacts in a similar manner. Public health policies focussed on perinatal health must consider the interaction between individual and area characteristics.