Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model

WOS: 000462721900029PubMed ID: 30926774Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2(-/- )mice, an effect mimicked by CD8(+) T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8(+) T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression.Georgia Cancer Center; Forbes Institute research fund; Bridge Fund by Augusta University Research Inc.; American Cancer Society Institutional fundWe gratefully acknowledge the generous help from Flow Cytometry, Genomics Core facilities, and Labaratory of Animal Services. We thank Drs. Rafi Ahmed and Paulo C. Rodriguez for insightful discussions and comments, Dr. Iskander Asm for for helping with and training of our staff on the tail vein injections. This work was supported by start up funds to H.K. by Georgia Cancer Center. Additional research fundings to H.K. provided by American Cancer Society Institutional fund, Forbes Institute research fund, and Bridge Fund by Augusta University Research Inc

Swedish high school students' knowledge and attitudes regarding fertility and family building

<p>Abstract</p> <p>Background</p> <p>Infertility is a serious problem for those who suffer. Some of the risks for infertility are preventable and the individual should therefore have knowledge of them. The purposes of this study were to investigate high-school students' knowledge about fertility, plans for family building and to compare views and knowledge between female and male students.</p> <p>Methods</p> <p>A questionnaire containing 34 items was answered by 274 students. Answers from male and female students were compared using student's <it>t</it>-test for normally distributed variables and Mann-Whitney <it>U</it>-test for non-normal distributions. The chi-square test was used to compare proportions of male and female students who answered questions on nominal and ordinal scales. Differences were considered as statistically significant at a <it>p</it>-value of 0.05.</p> <p>Results</p> <p>Analyses showed that 234 (85%) intended to have children. Female students felt parenthood to be significantly more important than male students: <it>p </it>= <it><</it>0.01. The mean age at which the respondents thought they would like to start to build their family was 26 (± 2.9) years. Men believed that women's fertility declined significantly later than women did: <it>p </it>= <it><</it>0.01. Women answered that 30.7% couples were involuntarily infertile and men answered 22.5%: <it>p </it>= <it><</it>0.01. Females thought it significantly more likely that they would consider IVF or adoption than men, <it>p = </it>0.01. Men felt they were more likely to abstain from having children than women: <it>p = <</it>0.01. Women believed that body weight influenced fertility significantly more often than men: <it>p = <</it>0.01 and men believed significantly more often that smoking influenced fertility: <it>p </it>= 0.03. Both female and male students answered that they would like to have more knowledge about the area of fertility.</p> <p>Conclusions</p> <p>Young people plan to start their families when the woman's fertility is already in decline. Improving young people's knowledge about these issues would give them more opportunity to take responsibility for their sexual health and to take an active role in shaping political change to improve conditions for earlier parenthood.</p

Le rôle des mécanismes épigénétiques impliqués dans la maintenance des cellules souches du cancer du sein

Une sous population de cellules au sein des tumeurs mammaires présente une capacité accrue de se renouveler et de reproduire l’hétérogénéité du cancer du sein. Maintenant il est bien connu que les cellules souches présomptives du cancer du sein possèdent des programmes d’expression des gènes qui correspondent à leurs caractéristiques biologiques uniques. Notre groupe a été impliqué dans la caractérisation épigénétique des cellules souches présomptives du cancer du sein et l’importance de la dérégulation des mécanismes épigénétiques comme la méthylation de l’ADN et le microARN au cours de la carcinogenèse. Plus spécifiquement cette étude détaille l’idée que la survie des cellules souches du cancer du sein peut être due à une signalisation via des circuits spécifiques de régulation, y compris la voie d’inflammation IL6-JAK-STAT. Ces cellules présentent une activation constitutive de cette voie associée à une configuration particulière de la chromatine. Une autre part de cette étude est d’explorer l’idée que des changements dans l’expression des microARN sont fondamentaux pour la maintenance des principales caractéristiques de ces cellules, et leur ciblage peut représenter une nouvelle approche de thérapie contre le cancer du sein. De plus, en testant directement les conséquences in vivo de la régulation de miR30a nous ouvrons la voie pour la recherche et la validation de l’utilisation potentielle des microARN comme thérapie anti cancéreuse. Ensemble, nos résultats apportent une nouvelle compréhension du rôle des modifications épigénétiques dans la maintenance des cellules souches du cancer du sein. De façon importante ces découvertes intègrent l’idée que des mécanismes de régulations différents mais coordonnés ont un rôle dans la survie des cellules souches du cancer du sien et donnent une perspective élargie pour la découverte de nouvelles cibles thérapeutiquesA subpopulation of cells within breast tumors is known to display an increased ability to self-renew and reproduce breast cancer cell heterogeneity. It is now known that putative breast cancer stem cells (CSCs) display distinct programs of gene expression that correlate with their unique biological characteristics. Our group has been involved in the epigenetic characterization of putative breast CSCs and the importance of the deregulation of epigenetic mechanisms such as DNA methylation and microRNA during carcinogenesis. More specifically, this study is detailing the idea that the survival of breast CSC may be dependent on signaling through specific regulatory circuits, including the well known inflammatory IL6-JAK-STAT pathway. These cells display a constitutive activation of this pathway associated with a distinct chromatin configuration. Another part of the study is exploring the idea that changes in microRNA expression are fundamental in sustaining the main attributes of these cells, and their targeting may represent a novel approach for breast cancer therapy. In addition, by directly testing the in vivo consequences of miR30a regulation, we open a window of opportunity for testing and validating the potential use of microRNAs in anti-neoplastic therapy. Together our results bring a new understanding of the role of epigenetic modifications in the maintenance of breast CSC. Importantly, these findings integrate the idea that different but coordinated regulation mechanisms play a role in the survival of CSC and give a larger perspective for finding novel therapeutic target

HAT cofactor TRRAP mediates β-Catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway

The Wnt pathway is a key regulator of embryonic development and stem cell self-renewal, and hyperactivation of the Wnt signalling is associated with many human cancers. The central player in the Wnt pathway is beta-catenin, a cytoplasmic protein whose function is tightly controlled by ubiquitination and degradation, however the precise regulation of beta-catenin stability/degradation remains elusive. Here, we report a new mechanism of beta-catenin ubiquitination acting in the context of chromatin. This mechanism is mediated by the histone acetyltransferase (HAT) complex component TRRAP and Skp1, an invariable component of the Skp-Cullin-F-box (SCF) ubiquitin ligase complex. TRRAP interacts with Skp1/SCF and mediates its recruitment to beta-catenin target promoter in chromatin. TRRAP deletion leads to a reduced level of beta-catenin ubiquitination, lower degradation rate and accumulation of beta-catenin protein. Furthermore, recruitment of Skp1 to chromatin and ubiquitination of chromatin-bound beta-catenin are abolished upon TRRAP knock-down, leading to an abnormal retention of beta-catenin at the chromatin and concomitant hyperactivation of the canonical Wnt pathway. These results demonstrate that there is a distinct regulatory mechanism for beta-catenin ubiquitination/ destruction acting in the nucleus which functionally complements cytoplasmic destruction of beta-catenin and prevents its oncogenic stabilization and chronic activation of the canonical Wnt pathway

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

International audienceSenescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context

Actualités en recherche en oncologie : l'essentiel du 4e Symposium International 2019 du Centre de Recherche en Cancérologie de Lyon

International audienc

Comprehensive characterization of claudin-low breast tumors reflects the impact of the cell-of-origin on cancer evolution

International audienceClaudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis

The pleiotropic effects of TNF alpha in breast cancer subtypes is regulated by TNFAIP3/A20 (vol 38, pg 469, 2018)

Following publication of this article the authors noted that the Acknowledgments section had been omitted. This section should read as follows.Georgia Cancer Center American Cancer Society Augusta University Research Inc. Forbes Institute research fun