Cancer biology: BET-ting on chromatin
Tumor development often involves genomic changes that affect protein expression, so chromatin alterations have received a lot of attention as possible therapeutic targets. A handful of recent studies support this idea by identifying a role for the bromodomain and extraterminal (BET) family of transcriptional regulators, which bind and recognize histone acetylation, in several human hematological malignancies.
Four independent groups—from Boston's Dana-Farber Cancer Institute, New York state's Cold Spring Harbor Laboratory, the UK's Cambridge University and Massachusetts's Constellation Pharmaceuticals—started from different points and used different models, but they all converged on the finding that interfering with the function of BET proteins reduces the transcription of key oncogenes such as Myc, arrests cell-cycle progression and leads to apoptosis (Cell 146, 904–917, 2011; Nature 478, 524–528 & 529–533, 2011; Proc. Natl. Acad. Sci. USA 108, 16669–16674, 2011).
Crucially, the four studies highlighted the clinical implications of this finding by showing that small-molecule inhibitors of BET family members had therapeutic effects in mouse models of leukemia, lymphoma and myeloma, as well as in primary cells isolated from people with cancer. —JCL
Friday, December 30, 2011
Wednesday, November 30, 2011
Man-made flu virus with potential to wipe out many millions if it ever escaped is created in research lab
A group of scientists is pushing to publish research about how they created a man-made flu virus that could potentially wipe out civilisation.
The deadly virus is a genetically tweaked version of the H5N1 bird flu strain, but is far more infectious and could pass easily between millions of people at a time.
The research has caused a storm of controversy and divided scientists, with some saying it should never have been carried out.
Tuesday, May 03, 2011
Apoptosis promotes early tumorigenesis
One hallmark of cancer is intrinsic or acquired resistance
to apoptosis. Surprisingly, recent studies demonstrate that
CD95/Fas/Apo1 and p53 upregulated mediator of apoptosis/
PUMA (potent inducers of the death receptor and the
mitochondrial apoptotic pathways, respectively) promote
tumorigenesis. These findings provide important insights
into the multifaceted roles of apoptosis in tumorigenesis.
http://www.nature.com/onc/journal/v30/n16/pdf/onc2010573a.pdf
to apoptosis. Surprisingly, recent studies demonstrate that
CD95/Fas/Apo1 and p53 upregulated mediator of apoptosis/
PUMA (potent inducers of the death receptor and the
mitochondrial apoptotic pathways, respectively) promote
tumorigenesis. These findings provide important insights
into the multifaceted roles of apoptosis in tumorigenesis.
http://www.nature.com/onc/journal/v30/n16/pdf/onc2010573a.pdf
Wednesday, April 20, 2011
EMT theory for metastases challenged during AACR
It can't be easy to stand in front of hundreds of colleagues and tell them that ten years of research has led them in the wrong direction. But at the annual meeting of the American Association for Cancer Research (AACR) earlier this month, pathologist David Tarin did just that, by challenging a leading hypothesis on how cancers metastasize...
PARA VER EL TEXTO COMPLETO GRATUITO
PARA VER EL TEXTO COMPLETO GRATUITO
Saturday, April 02, 2011
Academic bias & biotech failures
The unspoken rule is that at least 50% of the studies published even in top tier academic journals – Science, Nature, Cell, PNAS, etc… – can’t be repeated with the same conclusions by an industrial lab.
Artículo completo (libre acceso):
Artículo completo (libre acceso):
Monday, March 14, 2011
Whole genome sequencing of single tumor cells: A method to infer Tumor evolution? Nature 2011
Tumour evolution inferred by single-cell sequencing
Nature (2011) doi:10.1038/nature09807
Received 25 May 2010 Accepted 07 January 2011 Published online 13 March 2011
Nature (2011) doi:10.1038/nature09807
Received 25 May 2010 Accepted 07 January 2011 Published online 13 March 2011
Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis.
Oncogene. 2011 Mar 7. [Epub ahead of print]
Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis.
publication, 7 March 2011; doi:10.1038/onc.2011.28.
Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis.
publication, 7 March 2011; doi:10.1038/onc.2011.28.
Friday, March 11, 2011
Breast cancer: Luminal cells with an identity crisis
Breast cancer: Luminal cells with an identity crisis
Gemma K. Alderton
Abstract
Inherited mutations in BRCA1 seem to specifically increase the risk of developing basal-like breast cancers; so, Proia and colleagues investigated how BRCA1 might promote the formation of this subtype of breast cancer.Using samples from reduction mammoplasty (BRCA1+/+) and prophylactic mastectomy from individuals with BRCA1 mutations (BRCA1mut/+), Proia and colleagues transformed cell suspensions with four tumorigenic genes (TP53R175H, CCND1, PI3KCA and KRASG12V) that are
Gemma K. Alderton
Abstract
Inherited mutations in BRCA1 seem to specifically increase the risk of developing basal-like breast cancers; so, Proia and colleagues investigated how BRCA1 might promote the formation of this subtype of breast cancer.Using samples from reduction mammoplasty (BRCA1+/+) and prophylactic mastectomy from individuals with BRCA1 mutations (BRCA1mut/+), Proia and colleagues transformed cell suspensions with four tumorigenic genes (TP53R175H, CCND1, PI3KCA and KRASG12V) that are
Hallmarks of cancer: the next generation. Weinberg, Hanahan. Cell 2011. PDF
Cell. 2011 Mar 4;144(5):646-74.
Los hallmarks del cáncer propuestos desde hace varios años por Weinberg incorporan ahora otras características ya propuestas por otros múltiples veces como la inflamación, la necrosis, las alteraciones metabólicas entre otras.
Cell. 2011 Mar 4;144(5):646-74.
Los hallmarks del cáncer propuestos desde hace varios años por Weinberg incorporan ahora otras características ya propuestas por otros múltiples veces como la inflamación, la necrosis, las alteraciones metabólicas entre otras.
Tuesday, March 08, 2011
Thursday, March 03, 2011
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
top of page
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
Predictive, personalized, preventive, participatory (P4) cancer medicine
Leroy Hood & Stephen H. Friend About the authors
top of page
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
Monday, February 28, 2011
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.
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.
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.
Monday, February 21, 2011
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.
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.
Saturday, February 19, 2011
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.
2011 Abundant Human DNA Contamination Identified in Non-Primate Genome Databases. PLoS ONE 6(2): e16410.doi:10.1371/journal.pone.0016410
Thursday, February 10, 2011
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
Les dejo el link de un número completo de revisiones de cáncer.
http://onlinelibrary.wiley.com/doi/10.1002/path.v223.2/issuetoc
Wednesday, February 02, 2011
Interesante
Correlated genotypes in friendship networks.
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.
Sunday, January 23, 2011
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)
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