Epithelial mesenchymal transition traits in human breast cancer cell lines

Epithelial mesenchymal transition (EMT) has long been associated with breast cancer cell invasiveness and evidence of EMT processes in clinical samples is growing rapidly. Genome-wide transcriptional profiling of increasingly larger numbers of human breast cancer (HBC) cell lines have confirmed the existence of a subgroup of cell lines (termed Basal B/Mesenchymal) with enhanced invasive properties and a predominantly mesenchymal gene expression signature, distinct from subgroups with predominantly luminal (termed Luminal) or mixed basal/luminal (termed Basal A) features (Neve et al Cancer Cell 2006). Studies providing molecular and cellular analyses of EMT features in these cell lines are summarised, and the expression levels of EMT-associated factors in these cell lines are analysed. Recent clinical studies supporting the presence of EMT-like changes in vivo are summarised. Human breast cancer cell lines with mesenchymal properties continue to hold out the promise of directing us towards key mechanisms at play in the metastatic dissemination of breast cancer.

Defining the E-Cadherin repressor interactome in epithelial-mesenchymal transition : the PMC42 model as a case study

Epithelial-mesenchymal transition (EMT) is a feature of migratory cellular processes in all stages of life, including embryonic development and wound healing. Importantly, EMT features cluster with disease states such as chronic fibrosis and cancer. The dissolution of the E-cadherin-mediated adherens junction (AJ) is a key preliminary step in EMT and may occur early or late in the growing epithelial tumour. This is a first step for tumour cells towards stromal invasion, intravasation, extravasation and distant metastasis. The AJ may be inactivated in EMT by directed E-cadherin cleavage; however, it is increasingly evident that the majority of AJ changes are transcriptional and mediated by an expanding group of transcription factors acting directly or indirectly to repress E-cadherin expression. A review of the current literature has revealed that these factors may regulate each other in a hierarchical pattern where Snail1 (formerly Snail) and Snail2 (formerly Slug) are initially induced, leading to the activation of Zeb family members, TCF3, TCF4, Twist, Goosecoid and FOXC2. Within this general pathway, many inter-regulatory relationships have been defined which may be important in maintaining the EMT phenotype. This may be important given the short half-life of Snail1 protein. We have investigated these inter-regulatory relationships in the mesenchymal breast carcinoma cell line PMC42 (also known as PMC42ET) and its epithelial derivative, PMC42LA. This review also discusses several newly described regulators of E-cadherin repressors including oestrogen receptor-α and new discoveries in hypoxia- and growth factor-induced EMT. Finally, we evaluated how these findings may influence approaches to current cancer treatment.

Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer

As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as 'normal' breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finallyCan we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity.

Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment

Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancer-associated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44HI/CD24lO/-stem cell phenotype in human breast cancer

We review here the recently emerging relationship between epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSC), and provide analyses of published data on human breast cancer cell lines, supporting their utility as a model for the EMT/BCSC state. Genome-wide transcriptional profiling of these cell lines has confirmed the existence of a subgroup with mesenchymal tendencies and enhanced invasive properties ('Basal B'/Mesenchymal), distinct from subgroups with either predominantly luminal ('Luminal') or mixed basal/luminal ('Basal A') features (Neve et al. Cancer Cell, 2006). A literature-derived EMT gene signature has shown specific enrichment within the Basal B subgroup of cell lines, consistent with their over-expression of various EMT transcriptional drivers. Basal B cell lines are found to resemble BCSC, being CD44highCD24low. Moreover, gene products that distinguish Basal B from Basal A and Luminal cell lines (Basal B Discriminators) showed close concordance with those that define BCSC isolated from clinical material, as reported by Shipitsin et al. (Cancer Cell, 2007). CD24 mRNA levels varied across Basal B cell lines, correlating with other Basal B Discriminators. Many gene products correlating with CD24 status in Basal B cell lines were also differentially expressed in isolated BCSC. These findings confirm and extend the importance of the cellular product of the EMT with Basal B cell lines, and illustrate the value of analysing these cell lines for new leads that may improve breast cancer outcomes. Gene products specific to Basal B cell lines may serve as tools for the detection, quantification, and analysis of BCSC/EMT attributes.

Overview of INEX 2014

INEX investigates focused retrieval from structured documents by providing large test collections of structured documents, uniform evaluation measures, and a forum for organizations to compare their results. This paper reports on the INEX 2014 evaluation campaign, which consisted of three tracks: The Interactive Social Book Search Track investigated user information seeking behavior when interacting with various sources of information, for realistic task scenarios, and how the user interface impacts search and the search experience. The Social Book Search Track investigated the relative value of authoritative metadata and user-generated content for search and recommendation using a test collection with data from Amazon and LibraryThing, including user profiles and personal catalogues. The Tweet Contextualization Track investigated tweet contextualization, helping a user to understand a tweet by providing him with a short background summary generated from relevant Wikipedia passages aggregated into a coherent summary. INEX 2014 was an exciting year for INEX in which we for the third time ran our workshop as part of the CLEF labs. This paper gives an overview of all the INEX 2014 tracks, their aims and task, the built test-collections, the participants, and gives an initial analysis of the results.

Conference report : ‘For the Socially Responsible University’. Reflections on Universidad 2014, the 9th International Higher Education congress in Havana, Cuba, February 2014

This article describes salient aspects of 'Universidad', the 9th International Higher Education conference held in Havana, Cuba, in February 2014. Addressing the conference theme, 'For the Socially Responsible University', participants debated the university's capacity to lead societies in matters of knowledge creation and diffusion, and discussed how it could help governments in the quest for solutions to inequality and exclusion. A particularly interesting panel was one that discussed the social commitment of Hugo Chavez, the late president of Venezuela, and his work to support the expansion of education.

What’s best for our lymphoedema patients? Have we lost the patient as an individual in the quest for good science?

In a recent issue of the Journal of Lymphoedema, Nickolaidis and Karlsson (2013) indicated that most of the standard treatments for lymphoedema patients were explored and developed early last century, and suggested that holistic assessment of the individual is critical for good outcomes, but that perhaps “less emphasis should be placed on manual lymphatic drainage (MLD) and more on compression, exercise and weight reduction.”

How European public sector agencies innovate: The use of bottom-up, policy-dependent and knowledge-scanning innovation methods

Factor and cluster analysis are used to identify different methods that public sector agencies in Europeuse to innovate, based on data from a 2010 survey of 3273 agencies. The analyses identify three types ofinnovative agencies: bottom-up, knowledge-scanning, and policy-dependent. The distribution of bottom-up agencies across European countries is positively correlated with average per capita incomes while thedistribution of knowledge-scanning agencies is negatively correlated with income. In contrast, there isno consistent pattern by country in the distribution of policy-dependent agencies. Regression resultsthat control for agency characteristics find that innovation methods are significantly correlated with thebeneficial outcomes of innovation, with bottom-up and knowledge-scanning agencies out-performingpolicy-dependent agencies.

Bat species comparisons based on external morphology: A test of traditional versus geometric morphometric approaches

External morphology is commonly used to identify bats as well as to investigate flight and foraging behavior, typically relying on simple length and area measures or ratios. However, geometric morphometrics is increasingly used in the biological sciences to analyse variation in shape and discriminate among species and populations. Here we compare the ability of traditional versus geometric morphometric methods in discriminating between closely related bat species – in this case European horseshoe bats (Rhinolophidae, Chiroptera) – based on morphology of the wing, body and tail. In addition to comparing morphometric methods, we used geometric morphometrics to detect interspecies differences as shape changes. Geometric morphometrics yielded improved species discrimination relative to traditional methods. The predicted shape for the variation along the between group principal components revealed that the largest differences between species lay in the extent to which the wing reaches in the direction of the head. This strong trend in interspecific shape variation is associated with size, which we interpret as an evolutionary allometry pattern.