Showing 336015–336028 of 336,781 results for "Steven Wishart"

Journals 2009 EN

Elevated level of inhibin-α subunit is pro-tumourigenic and pro-metastatic and associated with extracapsular spread in advanced prostate cancer

P Balanathan · Elizabeth D. Williams · Hong Wang +5 more

The biological function of inhibin-alpha subunit (INH alpha) in prostate cancer (PCa) is currently unclear. A recent study associated elevated levels of INH alpha in PCa patients with a higher risk of recurrence. This prompted us to use clinical specimens and functional studies to investigate the pro-tumourigenic and pro-metastatic function of INH alpha. We conducted a cross-sectional study to determine a link between INH alpha expression and a number of clinicopathological parameters including Gleason score, surgical margin, extracapsular spread, lymph node status and vascular endothelial growth factor receptor-3 expression, which are well-established prognostic factors of PCa. In addition, using two human PCa cell lines (LNCaP and PC3) representing androgen-dependent and -independent PCa respectively, we investigated the biological function of elevated levels of INH alpha in advanced cancer. Elevated expression of INH alpha in primary PCa tissues showed a higher risk of PCa patients being positive for clinicopathological parameters outlined above. Over-expressing INH alpha in LNCaP and PC3 cells demonstrated two different and cell-type-specific responses. INH alpha-positive LNCaP demonstrated reduced tumour growth whereas INH alpha-positive PC3 cells demonstrated increased tumour growth and metastasis through the process of lymphangiogenesis. This study is the first to demonstrate a pro-tumourigenic and pro-metastatic function for INH alpha associated with androgen-independent stage of metastatic prostate disease. Our results also suggest that INH alpha expression in the primary prostate tumour can be used as a predictive factor for prognosis of PCa.

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Journals 2009 EN

Tamoxifen: the drug that came in from the cold

Luke HughesDavies · Carlos Caldas · G.C. Wishart

Despite the perception of many oncologists that tamoxifen is an inferior drug, and should be substituted by an aromatase inhibitor in post-menopausal women, the current evidence strongly supports the view that AIs should be used 2-3 years after tamoxifen to achieve the maximal overall survival (OS) advantage.

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Journals 2009 EN

Inflammatory breast carcinoma as a model of accelerated self-metastatic expansion by intravascular growth

Peter Vermeulen · Steven Van Laere · Luc Dirix

Sir, Enderling et al (2009) describe simulated tumour growth using an in silico model comprised of cancer stem and non-stem cells. Using this model, three kinetic parameters at the cellular level (cell death, proliferation and migration linked to the space available for growth) can be controlled to explain the population-level features of tumour growth, even in the absence of a heterogeneous environment. The results collectively show that migratory ability dominates tumour growth kinetics. Insufficient cell death or long-living non-stem progeny, both resulting in space constraints, impede migration and symmetrical stem cell division, and, in this way, tumour progression. The spatiotemporal evolution of the model is characterised by the phenomenon of self-metastasis (Norton and Massague, 2006), i.e., tumour growth with cluster formation, with only the stem-cell-initiated clusters persisting. Inflammatory breast cancer (IBC) belongs to the clinical group of locally advanced breast cancers, with an unfavourable outcome. Although a relatively rare entity (only about 5% of all patients with breast cancer have IBC), worldwide several groups have focused their research on IBC for the following reasons: (1) the therapeutic opportunities are limited and new approaches need to be developed; (2) awareness needs to be increased among health workers because early diagnosis improves the outcome; and (3) IBC can function as a model of fast local growth, because cancer cell populations occupy large fractions of the breast gland within weeks to months, and as a model of efficient metastasis, because almost all patients have lymph node metastases and about one-third have distant metastases at diagnosis. In this context, we would like to suggest that the biological features of IBC strongly support the in silico model of self-metastatic expansion as demonstrated by Enderling et al (2009). From a pathologist's point of view, IBC has a specific growth pattern with a central tumour mass surrounded by smaller nodules of carcinoma, which is in continuity with the central tumour and resembles the three-dimensional simulation of Figure 7 in Enderling's paper, but is also spread throughout the breast tissue and even in the dermis. The latter distant nodules are separated from the main tumour and from each other by normal breast parenchyma, and can be regarded as metastases within the breast. IBC is thus ‘less compact’ than non-IBC, leaving more available space for migration of cancer cells. The growth pattern of IBC clearly fits the self-metastatic expansion hypothesis, and additional histological characteristics and the results of molecular studies of IBC further support this. In the breast parenchyma separating the tumour nodules, numerous intravascular tumour emboli can be observed, which is a well-established hallmark of IBC. Small areas of invasive carcinoma sometimes surround the intravascular tumour emboli. Regarding the kinetic parameters of the cellular level of the Enderling model, we propose that tumour emboli in blood vessels and lymph vessels represent significant cell movement throughout the breast gland, with a high μ value, through growth in the intravascular space. This intravascular growth has been observed in the MARY-X animal model of IBC and is based on strong homotypic interactions between the tumour cells by overexpression of E-cadherin (Alpaugh et al, 1999). Extravasation can occur actively, or, passively by volume increase resulting in rupture of the vessel wall, giving rise to a self-metastatic clone. In addition to the efficient migration of tumour cells in the vasculature of the breast gland, genome-wide gene expression profiling shows that IBC has overexpressed signalling pathways related to cell migration, which can lead to the ‘fingering morphologies’ at the edge of the main tumour mass. The insulin-like growth factor signalling is increased in IBC (Van Laere et al, 2007), leading to RhoC activation, one of the first molecular alterations that has been related to IBC and is responsible for increased cell motility (van Golen et al, 1999). NF-κB up-regulation, another established molecular characteristic of IBC, enhances tumour cell migration by inducing the mesenchymal cell behaviour of epithelial cells (Van Laere et al, 2006). An equally important condition in the self-metastasis model is the presence of cancer stem cells that are capable of migrating in less dense space to form separate tumour cell clusters; in the in silico model, only clones initiated by such stem cells survive. IBC clearly complies with these conditions as well. The lymphovascular emboli in animal models of IBC express a stem cell-like phenotype (Xiao et al, 2008). In human samples of IBC, the emboli are large and often have central necrosis and express CAIX as a marker of hypoxia, a condition in favour of a stem cell niche (Colpaert et al, 2003) The gene expression signature of IBC in patients contains stem cell gene expression patterns (Van Laere et al, 2008). In conclusion, we believe that the fact that IBC has fast growth in the breast gland, combined with a specific growth pattern (intravascular tumour expansion and enhanced cell migration) and numerous metastases at diagnosis, corroborates the self-metastatic expansion model. The design of a new multimodality treatment for patients with IBC, and with breast cancer in general, probably has to implement the interactions of the treatment with the balance between proliferation and cell death, on the one hand, and migration in available space, on the other hand, taking into account both the stem and non-stem cell populations.

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Journals 2009 EN

Molecular characteristics of screen-detected vs symptomatic breast cancers and their impact on survival

SarahJane Dawson · S W Duffy · Fiona M. Blows +7 more

Several recent studies have shown that screen detection remains an independent prognostic factor after adjusting for disease stage at presentation. This study compares the molecular characteristics of screen-detected with symptomatic breast cancers to identify if differences in tumour biology may explain some of the survival benefit conferred by screen detection.

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Journals 2009 EN

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Ian Tomlinson · Malcolm G. Dunlop · Harry Campbell +48 more

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

Springer Nature
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