Increased entropy of signal transduction in the cancer metastasis phenotype

Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis. Further exploration of such integrated cancer expression and protein interaction networks will therefore be a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table

On dynamic network entropy in cancer

The cellular phenotype is described by a complex network of molecular interactions. Elucidating network properties that distinguish disease from the healthy cellular state is therefore of critical importance for gaining systems-level insights into disease mechanisms and ultimately for developing improved therapies. By integrating gene expression data with a protein interaction network to induce a stochastic dynamics on the network, we here demonstrate that cancer cells are characterised by an increase in the dynamic network entropy, compared to cells of normal physiology. Using a fundamental relation between the macroscopic resilience of a dynamical system and the uncertainty (entropy) in the underlying microscopic processes, we argue that cancer cells will be more robust to random gene perturbations. In addition, we formally demonstrate that gene expression differences between normal and cancer tissue are anticorrelated with local dynamic entropy changes, thus providing a systemic link between gene expression changes at the nodes and their local network dynamics. In particular, we also find that genes which drive cell-proliferation in cancer cells and which often encode oncogenes are associated with reductions in the dynamic network entropy. In summary, our results support the view that the observed increased robustness of cancer cells to perturbation and therapy may be due to an increase in the dynamic network entropy that allows cells to adapt to the new cellular stresses. Conversely, genes that exhibit local flux entropy decreases in cancer may render cancer cells more susceptible to targeted intervention and may therefore represent promising drug targets.Comment: 10 pages, 3 figures, 4 tables. Submitte

The clinical and functional significance of c-Met in breast cancer: a review

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.CMH-Y is funded by a Cancer Research UK Clinical Research Fellowship. JLJ is funded by the Breast Cancer Campaign Tissue Bank

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

The Met oncogene and basal-like breast cancer: another culprit to watch out for?

Recent findings suggest the involvement of the MET oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor, in the onset and progression of basal-like breast carcinoma. The expression profiles of basal-like tumors - but not those of other breast cancer subtypes - are enriched for gene sets that are coordinately over-represented in transcriptional signatures regulated by Met. Consistently, tissue microarray analyses have revealed that Met immunoreactivity is much higher in basal-like cases of human breast cancer than in other tumor types. Finally, mouse models expressing mutationally activated forms of Met develop a high incidence of mammary tumors, some of which exhibit basal characteristics. The present review summarizes current knowledge on the role and activity of Met in basal-like breast cancer, with a special emphasis on the correlation between this tumor subtype and the cellular hierarchy of the normal mammary gland

Molecular interactions between Hel2 and RNA supporting ribosome-associated quality control

Ribosome-associated quality control (RQC) pathways monitor and respond to stalling of the translating ribosome. Here the authors show that the ribosome associated RQC factor Hel2/ZNF598, an E3 ubiquitin ligase, generally interacts with mRNAs in the vicinity of stop codons

Human macrophage colony-stimulating factor is expressed at and shed from the cell surface

Abstract Surface membrane-associated growth factors are being recognized as important for developmental processes, including cell assembly, differentiation, and growth. To investigate the role of membrane-bound macrophage colony-stimulating factor (M-CSF) in myelopoiesis, and whether this factor is released from the cell surface in association with shed membrane-derived vesicles, COS-1 cells were transfected with cDNAs for M-CSF-tau (containing the transmembrane domain) or a soluble mutant form of the molecule lacking the transmembrane domain ([s]M-CSF- alpha). COS-1 cells transfected with either cDNA released activity into the spent culture medium. Conditioned medium was separated by centrifugation into supernatants and pellets were found to contain plasma membrane-derived vesicles by transmission electron microscopy. When medium fractions were assayed in marrow cultures, activity was localized to shed plasma membrane-derived vesicles in medium conditioned by cells transfected with cDNA for M-CSF-tau and in the vesicle-free supernatants of medium conditioned by cells transfected with cDNA for [s]M-CSF-alpha. In addition, nuclear, mitochondrial, and plasma membrane subfractions of stably transfected cells were prepared and assayed for activity. Concentration-dependent stimulation of macrophage colony formation was observed with purified plasma membranes (but not nuclear or cytosolic proteins) from cells transfected with cDNA for M-CSF-tau. By contrast, membranes from untransfected cells and cells transfected with cDNA for [s]M-CSF-alpha or control DNA expressed no activity. Together, the data indicate that human M-CSF is expressed at the cell surface and exfoliated in association with surface membrane- derived vesicles.</jats:p

Human macrophage colony-stimulating factor is expressed at and shed from the cell surface

Surface membrane-associated growth factors are being recognized as important for developmental processes, including cell assembly, differentiation, and growth. To investigate the role of membrane-bound macrophage colony-stimulating factor (M-CSF) in myelopoiesis, and whether this factor is released from the cell surface in association with shed membrane-derived vesicles, COS-1 cells were transfected with cDNAs for M-CSF-tau (containing the transmembrane domain) or a soluble mutant form of the molecule lacking the transmembrane domain ([s]M-CSF- alpha). COS-1 cells transfected with either cDNA released activity into the spent culture medium. Conditioned medium was separated by centrifugation into supernatants and pellets were found to contain plasma membrane-derived vesicles by transmission electron microscopy. When medium fractions were assayed in marrow cultures, activity was localized to shed plasma membrane-derived vesicles in medium conditioned by cells transfected with cDNA for M-CSF-tau and in the vesicle-free supernatants of medium conditioned by cells transfected with cDNA for [s]M-CSF-alpha. In addition, nuclear, mitochondrial, and plasma membrane subfractions of stably transfected cells were prepared and assayed for activity. Concentration-dependent stimulation of macrophage colony formation was observed with purified plasma membranes (but not nuclear or cytosolic proteins) from cells transfected with cDNA for M-CSF-tau. By contrast, membranes from untransfected cells and cells transfected with cDNA for [s]M-CSF-alpha or control DNA expressed no activity. Together, the data indicate that human M-CSF is expressed at the cell surface and exfoliated in association with surface membrane- derived vesicles.</jats:p