Special issue of Nature Reviews Clinical Oncology on personalized medicine, includes essay from L. Hood, S. Friend:

OPINION:
Predictive, personalized, preventive, participatory (P4) cancer medicine
Leroy Hood & Stephen H. Friend About the authors

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Abstract
Medicine will move from a reactive to a proactive discipline over the next decade—a discipline that is predictive, personalized, preventive and participatory (P4). P4 medicine will be fueled by systems approaches to disease, emerging technologies and analytical tools. There will be two major challenges to achieving P4 medicine—technical and societal barriers—and the societal barriers will prove the most challenging. How do we bring patients, physicians and members of the health-care community into alignment with the enormous opportunities of P4 medicine? In part, this will be done by the creation of new types of strategic partnerships—between patients, large clinical centers, consortia of clinical centers and patient-advocate groups. For some clinical trials it will necessary to recruit very large numbers of patients—and one powerful approach to this challenge is the crowd-sourced recruitment of patients by bringing large clinical centers together with patient-advocate groups.

FULL TEXT:
http://www.nature.com/nrclinonc/journal/v8/n3/full/nrclinonc.2010.227.html

p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs

Nature Cell Biology (2011) doi:10.1038/ncb2173

The epithelial–mesenchymal transition (EMT) has recently been linked to stem cell phenotype1, 2. However, the molecular mechanism underlying EMT and regulation of stemness remains elusive. Here, using genomic approaches, we show that tumour suppressor p53 has a role in regulating both EMT and EMT-associated stem cell properties through transcriptional activation of the microRNA miR-200c. p53 transactivates miR-200c through direct binding to the miR-200c promoter. Loss of p53 in mammary epithelial cells leads to decreased expression of miR-200c and activates the EMT programme, accompanied by an increased mammary stem cell population. Re-expressing miR-200c suppresses genes that mediate EMT and stemness properties3, 4 and thereby reverts the mesenchymal and stem-cell-like phenotype caused by loss of p53 to a differentiated epithelial cell phenotype. Furthermore, loss of p53 correlates with a decrease in the level of miR-200c, but an increase in the expression of EMT and stemness markers, and development of a high tumour grade in a cohort of breast tumours. This study elucidates a role for p53 in regulating EMT–MET (mesenchymal–epithelial transition) and stemness or differentiation plasticity, and reveals a potential therapeutic implication to suppress EMT-associated cancer stem cells through activation of the p53–miR-200c pathway.

A Functional Role for Tumor Cell Heterogeneity in a Mouse Model of Small Cell Lung Cancer

Cancer Cell, Volume 19, Issue 2, 244-256, 15 February 2011
Summary

Small cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic RasV12. Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties.

Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.

Nature. 2011 Feb 16. [Epub ahead of print]
Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.
Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M.
1] Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, 9500 Gilman Drive, Mail Code 0723, La Jolla, California 92093, USA [2] Pfizer Oncology Research Unit West, San Diego, California 92121, USA. [3].
Abstract
Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-κB (IκB) kinase-α (IKK-α), a protein kinase that is needed for the self-renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-α are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(+)CD25(+) T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)(+) stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK(+) human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4(+) or FOXP3(+) T cells on human breast cancer prognosis and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.

Abundant Human DNA Contamination Identified in Non-Primate Genome Databases

During routine screens of the NCBI databases using human repetitive elements we discovered an unlikely level of nucleotide identity across a broad range of phyla. To ascertain whether databases containing DNA sequences, genome assemblies and trace archive reads were contaminated with human sequences, we performed an in depth search for sequences of human origin in non-human species. Using a primate specific SINE, AluY, we screened 2,749 non-primate public databases from NCBI, Ensembl, JGI, and UCSC and have found 492 to be contaminated with human sequence. These represent species ranging from bacteria (B. cereus) to plants (Z. mays) to fish (D. rerio) with examples found from most phyla. The identification of such extensive contamination of human sequence across databases and sequence types warrants caution among the sequencing community in future sequencing efforts, such as human re-sequencing. We discuss issues this may raise as well as present data that gives insight as to how this may be occurring.

Longo MS, O'Neill MJ, O'Neill RJ, 2011 Abundant Human DNA Contamination Identified in Non-Primate Genome Databases. PLoS ONE 6(2): e16410.doi:10.1371/journal.pone.0016410

Numero acceso libre cancer

Hola
Les dejo el link de un número completo de revisiones de cáncer.
http://onlinelibrary.wiley.com/doi/10.1002/path.v223.2/issuetoc

Interesante

Correlated genotypes in friendship networks.  doi 10.1073/pnas.1011687108

1. James H. Fowler^a,^b,¹,
2. Jaime E. Settle^b, and
3. Nicholas A. Christakis^c,^d

Abstract

It is well known that humans tend to associate with other humans who have similar characteristics, but it is unclear whether this tendency has consequences for the distribution of genotypes in a population. Although geneticists have shown that populations tend to stratify genetically, this process results from geographic sorting or assortative mating, and it is unknown whether genotypes may be correlated as a consequence of nonreproductive associations or other processes. Here, we study six available genotypes from the National Longitudinal Study of Adolescent Health to test for genetic similarity between friends. Maps of the friendship networks show clustering of genotypes and, after we apply strict controls for population stratification, the results show that one genotype is positively correlated (homophily) and one genotype is negatively correlated (heterophily). A replication study in an independent sample from the Framingham Heart Study verifies that DRD2 exhibits significant homophily and that CYP2A6 exhibits significant heterophily. These unique results show that homophily and heterophily obtain on a genetic (indeed, an allelic) level, which has implications for the study of population genetics and social behavior. In particular, the results suggest that association tests should include friends’ genes and that theories of evolution should take into account the fact that humans might, in some sense, be metagenomic with respect to the humans around them.

Nuevo papel para las IAPs

Caspase control: IAPs as NEDD8 E3 ligases

A new role of inhibitor of apoptosis (IAP) proteins in caspase regulation is revealed: they can promote conjugation of the ubiquitin-like protein NEDD8 as well as ubiquitin. This adds to the complexity of IAP-mediated signaling.

Inhibitor of apoptosis (IAP) proteins act as ubiquitin E3 ligases and regulate caspase activity through ubiquitin-mediated proteasomal degradation; deubiquitylating enzymes (DUBs) can reverse the activity of ubiquitin and ubiquitin-like (UBL) proteins, such as NEDD8. In transgenic Drosophila expressing IAP antagonists to induce apoptosis, Broemer et al. have now systemically knocked down individual DUBs using RNA interference and identified three NEDD8-specific proteases that, when knocked down, suppress cell death in vivo.

Apoptosis was reduced in the null mutants of one of these genes, Deneddylase 1 (DEN1), and the effector caspase drICE was found to be neddylated in vivo, which suggested a role for NEDD8 in apoptosis. Interestingly, UV mediated reduction in Drosophila IAP 1 (DIAP1) protein levels reduced neddylation of drICE and induced apoptosis, indicating that DIAP1 is a NEDD8 E3 ligase for drICE.

Further investigation showed that DIAP1 neddylates drICE in a RING- and binding-dependent manner leading to reduced drICE proteolytic activity, and further mass spectrometry analysis identified nine lysine residues in drICE as sites for neddylation.

As XIAP, a mammalian IAP, also promoted neddylation of caspase 7 in a RING-dependent manner, IAP-mediated neddylation seems to be evolutionarily conserved.

This study demonstrates that IAPs can function as E3 ligases for NEDD8 as well as for ubiquitin and extends the complexity of IAP-mediated signaling.

Iley Ozerlat
Signaling Gateway

Reference:
Broemer M. et al.
Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases.
Mol. Cell 40, 810-812 (2010)
Full text

Abierto al Público

Hola

He abierto el blog para ser visualizado de manera abierta

Malignant cells facilitate lung metastasis by bringing their own soil.

Proc Natl Acad Sci U S A. 2010 Nov 22. [Epub ahead of print]
Malignant cells facilitate lung metastasis by bringing their own soil.
Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D, Jain RK.

Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Abstract
Metastatic cancer cells (seeds) preferentially grow in the secondary sites with a permissive microenvironment (soil). We show that the metastatic cells can bring their own soil-stromal components including activated fibroblasts-from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that viability of circulating metastatic cancer cells is higher if they are incorporated in heterotypic tumor-stroma cell fragments. Moreover, we show that these cotraveling stromal cells provide an early growth advantage to the accompanying metastatic cancer cells in the lungs. Consistent with this hypothesis, we demonstrate that partial depletion of the carcinoma-associated fibroblasts, which spontaneously spread to the lung tissue along with metastatic cancer cells, significantly decreases the number of metastases and extends survival after primary tumor resection. Finally, we show that the brain metastases from lung carcinoma and other carcinomas in patients contain carcinoma-associated fibroblasts, in contrast to primary brain tumors or normal brain tissue. Demonstration of the direct involvement of primary tumor stroma in metastasis has important conceptual and clinical implications for the colonization step in tumor progression.

Saber cuando aumentar los analgésicos a ratones de experimentación

BRIEF COMMUNICATION
Nature Methods 7, 447–449 (1 June 2010) | doi:10.1038/nmeth.1455

http://www.nature.com/news/2010/100509/full/news.2010.228.html

Coding of facial expressions of pain in the laboratory mouse

Dale J Langford , Andrea L Bailey , Mona Lisa Chanda , Sarah E Clarke , Tanya E Drummond , Stephanie Echols , Sarah Glick , Joelle Ingrao , Tammy Klassen-Ross , Michael L LaCroix-Fralish , Lynn Matsumiya , Robert E Sorge , Susana G Sotocinal , John M Tabaka , David Wong , Arn M J M van den Maagdenberg , Michel D Ferrari , Kenneth D Craig & Jeffrey S Mogil

Abstract
Facial expression is widely used as a measure of pain in infants; whether nonhuman animals display such pain expressions has never been systematically assessed. We developed the mouse grimace scale (MGS), a standardized behavioral coding system with high accuracy and reliability; assays involving noxious stimuli of moderate duration are accompanied by facial expressions of pain.

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.

Science. 2010 Nov 5;330(6005):831-5.
Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.
Wallace BD, Wang H, Lane KT, Scott JE, Orans J, Koo JS, Venkatesh M, Jobin C, Yeh LA, Mani S, Redinbo MR.

Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Comment in:

Science. 2010 Nov 5;330(6005):766-7.
Abstract
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.