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.
Friday, November 26, 2010
Wednesday, November 24, 2010
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.
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.
Tuesday, November 23, 2010
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.
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.
Wednesday, November 17, 2010
Phenotypic Heterogeneity among Tumorigenic Melanoma Cells from Patients that Is Reversible and Not Hierarchically Organized.
Cancer Cell. 2010 Nov 16;18(5):510-23.
Phenotypic Heterogeneity among Tumorigenic Melanoma Cells from Patients that Is Reversible and Not Hierarchically Organized.
Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM, Morrison SJ.
Howard Hughes Medical Institute; Life Sciences Institute; Department of Internal Medicine; Center for Stem Cell Biology.
Abstract
We investigated whether melanoma is hierarchically organized into phenotypically distinct subpopulations of tumorigenic and nontumorigenic cells or whether most melanoma cells retain tumorigenic capacity, irrespective of their phenotype. We found 28% of single melanoma cells obtained directly from patients formed tumors in NOD/SCID IL2Rγ(null) mice. All stage II, III, and IV melanomas obtained directly from patients had common tumorigenic cells. All tumorigenic cells appeared to have unlimited tumorigenic capacity on serial transplantation. We were unable to find any large subpopulation of melanoma cells that lacked tumorigenic potential. None of 22 heterogeneously expressed markers, including CD271 and ABCB5, enriched tumorigenic cells. Some melanomas metastasized in mice, irrespective of whether they arose from CD271(-) or CD271(+) cells. Many markers appeared to be reversibly expressed by tumorigenic melanoma cells.
Significance
In cancers that follow a stem cell model, phenotypically distinct tumorigenic cells form abundant and phenotypically diverse nontumorigenic progeny in a hierarchical manner that resembles normal stem cell differentiation. In contrast to this model, our results indicate that primary cutaneous or metastatic melanomas from patients have common and phenotypically diverse tumorigenic cells that undergo reversible phenotypic changes in vivo. Most of the phenotypic heterogeneity in mela- noma is therefore not associated with a loss of tumorigenic potential or organized in stable hierarchies. These data suggest a phenotypic plasticity model in which phenotypic heterogeneity is driven largely by reversible changes within lineages of tumorigenic cells rather than by irreversible epigenetic or genetic changes.
http://www.cell.com/cancer-cell/fulltext/S1535-6108(10)00416-2
Phenotypic Heterogeneity among Tumorigenic Melanoma Cells from Patients that Is Reversible and Not Hierarchically Organized.
Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM, Morrison SJ.
Howard Hughes Medical Institute; Life Sciences Institute; Department of Internal Medicine; Center for Stem Cell Biology.
Abstract
We investigated whether melanoma is hierarchically organized into phenotypically distinct subpopulations of tumorigenic and nontumorigenic cells or whether most melanoma cells retain tumorigenic capacity, irrespective of their phenotype. We found 28% of single melanoma cells obtained directly from patients formed tumors in NOD/SCID IL2Rγ(null) mice. All stage II, III, and IV melanomas obtained directly from patients had common tumorigenic cells. All tumorigenic cells appeared to have unlimited tumorigenic capacity on serial transplantation. We were unable to find any large subpopulation of melanoma cells that lacked tumorigenic potential. None of 22 heterogeneously expressed markers, including CD271 and ABCB5, enriched tumorigenic cells. Some melanomas metastasized in mice, irrespective of whether they arose from CD271(-) or CD271(+) cells. Many markers appeared to be reversibly expressed by tumorigenic melanoma cells.
Significance
In cancers that follow a stem cell model, phenotypically distinct tumorigenic cells form abundant and phenotypically diverse nontumorigenic progeny in a hierarchical manner that resembles normal stem cell differentiation. In contrast to this model, our results indicate that primary cutaneous or metastatic melanomas from patients have common and phenotypically diverse tumorigenic cells that undergo reversible phenotypic changes in vivo. Most of the phenotypic heterogeneity in mela- noma is therefore not associated with a loss of tumorigenic potential or organized in stable hierarchies. These data suggest a phenotypic plasticity model in which phenotypic heterogeneity is driven largely by reversible changes within lineages of tumorigenic cells rather than by irreversible epigenetic or genetic changes.
http://www.cell.com/cancer-cell/fulltext/S1535-6108(10)00416-2
Monday, November 08, 2010
CD4(+) T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation.
Cancer Cell. 2010 Oct 27. [Epub ahead of print]
CD4(+) T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation.
Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Crosby E, Ryeom S, Felsher DW.
Division of Oncology, Departments of Medicine, Pathology and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract
Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.
CD4(+) T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation.
Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Crosby E, Ryeom S, Felsher DW.
Division of Oncology, Departments of Medicine, Pathology and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract
Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Science. 2010 Nov 5;330(6005):827-30.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Abstract
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Abstract
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Science. 2010 Nov 5;330(6005):827-30.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Abstract
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Abstract
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Science. 2010 Nov 5;330(6005):827-30.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Abstract
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-{alpha}.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Abstract
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Tuesday, November 02, 2010
Intracellular antibodies mediate cytosolic immune response!
Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21)
PNAS Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved October 12, 2010 (received for review September 19, 2010. Ahead of Print)
Donna L. Mallerya,1, William A. McEwana,1, Susanna R. Bidgooda,1, Greg J. Towersb, Chris M. Johnsona, and Leo C. Jamesa,2
Abstract
Antibodies provide effective antiviral immunity despite the fact that viruses escape into cells when they infect. Here we show that antibodies remain attached to viruses after cell infection and mediate an intracellular immune response that disables virions in the cytosol. We have discovered that cells possess a cytosolic IgG receptor, tripartite motif-containing 21 (TRIM21), which binds to antibodies with a higher affinity than any other IgG receptor in the human body. TRIM21 rapidly recruits to incoming antibody-bound virus and targets it to the proteasome via its E3 ubiquitin ligase activity. Proteasomal targeting leads to rapid degradation of virions in the cytosol before translation of virally encoded genes. Infection experiments demonstrate that at physiological antibody concentrations TRIM21 neutralizes viral infection. These results reveal an intracellular arm of adaptive immunity in which the protection mediated by antibodies does not end at the cell membrane but continues inside the cell to provide a last line of defense against infection.
PNAS Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved October 12, 2010 (received for review September 19, 2010. Ahead of Print)
Donna L. Mallerya,1, William A. McEwana,1, Susanna R. Bidgooda,1, Greg J. Towersb, Chris M. Johnsona, and Leo C. Jamesa,2
Abstract
Antibodies provide effective antiviral immunity despite the fact that viruses escape into cells when they infect. Here we show that antibodies remain attached to viruses after cell infection and mediate an intracellular immune response that disables virions in the cytosol. We have discovered that cells possess a cytosolic IgG receptor, tripartite motif-containing 21 (TRIM21), which binds to antibodies with a higher affinity than any other IgG receptor in the human body. TRIM21 rapidly recruits to incoming antibody-bound virus and targets it to the proteasome via its E3 ubiquitin ligase activity. Proteasomal targeting leads to rapid degradation of virions in the cytosol before translation of virally encoded genes. Infection experiments demonstrate that at physiological antibody concentrations TRIM21 neutralizes viral infection. These results reveal an intracellular arm of adaptive immunity in which the protection mediated by antibodies does not end at the cell membrane but continues inside the cell to provide a last line of defense against infection.
Monday, November 01, 2010
Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
Nature. 2010 Oct 28;467(7319):1114-7.
Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA.
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Comment in:
Nature. 2010 Oct 28;467(7319):1053-5.
Abstract
Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA.
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Comment in:
Nature. 2010 Oct 28;467(7319):1053-5.
Abstract
Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
DNA damage-mediated induction of a chemoresistant niche.
Cell. 2010 Oct 29;143(3):355-66.
DNA damage-mediated induction of a chemoresistant niche.
Gilbert LA, Hemann MT.
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract
While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action. PAPERFLICK:
DNA damage-mediated induction of a chemoresistant niche.
Gilbert LA, Hemann MT.
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract
While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action. PAPERFLICK:
Tuesday, October 26, 2010
TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.
Nature. 2010 Oct 21;467(7318):986-90.
TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.
Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, Flores ER.
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Abstract
Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.
TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.
Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, Flores ER.
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Abstract
Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.
Monday, September 27, 2010
O(2) regulates stem cells through Wnt/β-catenin signalling.
Nat Cell Biol. 2010 Sep 19. [Epub ahead of print]
O(2) regulates stem cells through Wnt/β-catenin signalling.
Mazumdar J, O'Brien WT, Johnson RS, Lamanna JC, Chavez JC, Klein PS, Simon MC.
[1] Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. [2] Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. [3] Current address: Clinical Biomarkers, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Abstract
Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (< 5% O(2)) have revealed strong regulatory links between O(2) availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O(2) gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1α (HIF-1α), a principal mediator of hypoxic adaptations, modulates Wnt/β-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing β-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/β-catenin activity is closely associated with low O(2) regions in the subgranular zone of the hippocampus, a key NSC niche. Hif-1α deletion impairs hippocampal Wnt-dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/β-catenin signalling in the subgranular zone. O(2) availability, therefore, may have a direct role in stem cell regulation through HIF-1α modulation of Wnt/β-catenin signalling.
O(2) regulates stem cells through Wnt/β-catenin signalling.
Mazumdar J, O'Brien WT, Johnson RS, Lamanna JC, Chavez JC, Klein PS, Simon MC.
[1] Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. [2] Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. [3] Current address: Clinical Biomarkers, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Abstract
Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (< 5% O(2)) have revealed strong regulatory links between O(2) availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O(2) gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1α (HIF-1α), a principal mediator of hypoxic adaptations, modulates Wnt/β-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing β-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/β-catenin activity is closely associated with low O(2) regions in the subgranular zone of the hippocampus, a key NSC niche. Hif-1α deletion impairs hippocampal Wnt-dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/β-catenin signalling in the subgranular zone. O(2) availability, therefore, may have a direct role in stem cell regulation through HIF-1α modulation of Wnt/β-catenin signalling.
Friday, September 10, 2010
Reactive Astrocytes Protect Melanoma Cells from Chemotherapy by Sequestering Intracellular Calcium through Gap Junction Communication Channels.
Neoplasia. 2010 Sep;12(9):748-54.
Thursday, September 02, 2010
Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer
Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer
Aleix Prat 
, Joel S Parker , Olga Karginova , Cheng Fan , Chad Livasy , Jason I Herschkowitz , Xiaping He and Charles M Perou
Breast Cancer Research 2010, 12:R68doi:10.1186/bcr2635
| Published: | 2 September 2010 |
Abstract (provisional)
Introduction
In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype.
Methods
The clinical, pathological and biological features of claudin-low tumors were compared to the other tumor subtypes using an updated human tumor database and multiple independent data sets. These main features of claudin-low tumors were also evaluated in a panel of breast cancer cell lines and genetically engineered mouse models.
Results
Claudin-low tumors are characterized by the low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes and cancer stem cell-like features. Clinically, the majority of claudin-low tumors are poor prognosis estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and epidermal growth factor receptor 2 (HER2)-negative (triple negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Interestingly, we show that a group of highly utilized breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell.
Conclusions
These results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines.
Monday, August 16, 2010
Thursday, August 12, 2010
http://www.biotechniques.com/news/biotechniquesNews/biotechniques-301169.html
Next generation sorting: FRET adapted for high throughput stem cell sorting
08/12/2010 Andrew S. Wiecek
A FRET-based method to purify stem cell cultures paves the way for the next generation of cell sorting.
Seria muy interesante para el estudio de celulas troncales de cancer.
http://www.biotechniques.com/news/biotechniquesNews/biotechniques-301169.html
08/12/2010 Andrew S. Wiecek
A FRET-based method to purify stem cell cultures paves the way for the next generation of cell sorting.
Seria muy interesante para el estudio de celulas troncales de cancer.
http://www.biotechniques.com/news/biotechniquesNews/biotechniques-301169.html
Thursday, July 22, 2010
No todo en Sudáfrica es fútbol
Investigadores sostienen que un gel bajo prueba en Sudáfrica disminuyó de forma sustancial el riesgo de infección de VIH-SIDA entre mujeres que lo utilizaron consistentemente antes de tener relaciones sexuales.
Un estudio dado a conocer este lunes 19 de julio, por el Centro para el Programa de Investigación del SIDA de Sudáfrica (CAPRISA) indica que el gel microbicida basado en el fármaco tenofovir redujo la tasa de infección de VIH en un 39% en un grupo de casi 900 voluntarias a lo largo de dos años y medio.
La investigación presentada en la XVIII Conferencia internacional sobre el SIDA en Viena también constató que el gel redujo en un 51% la tasa de infección del herpes simplex virus-2.
La Organización Mundial de la Salud (OMS) y ONUSIDA calificaron la noticia como un avance revolucionario.
Tuesday, June 22, 2010
Correciones y nuevos blancos...
The most important issue when trying to find mutations that cause disease via DNA sequencing is to keep the sequencing error rate as low as possible.
Whole-genome sequencing of DNA from two children with Mendelian disorders and from their healthy parents allows efficient correction of sequencing errors and the identification of causal genes.
http://www.nature.com/nmeth/journal/v7/n5/full/nmeth0510-350.html
Whole-genome sequencing of DNA from two children with Mendelian disorders and from their healthy parents allows efficient correction of sequencing errors and the identification of causal genes.
Nature Methods 7, 350 (2010)
doi:10.1038/nmeth0510-350
http://www.nature.com/nmeth/journal/v7/n5/full/nmeth0510-350.html
Friday, May 21, 2010
Creación de una célula bacteriana controlada por un genoma sintetizado químicamente.
Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
Craig Venter
Craig Venter
We report the design, synthesis and assembly of the 1.08-
Mbp Mycoplasma mycoides JCVI-syn1.0 genome starting
from digitized genome sequence information and its
transplantation into a Mycoplasma capricolum recipient
cell to create new Mycoplasma mycoides cells that are
controlled only by the synthetic chromosome. The only
DNA in the cells is the designed synthetic DNA sequence,
including “watermark” sequences and other designed
gene deletions and polymorphisms, and mutations
acquired during the building process. The new cells have
expected phenotypic properties and are capable of
continuous self-replication.
Mbp Mycoplasma mycoides JCVI-syn1.0 genome starting
from digitized genome sequence information and its
transplantation into a Mycoplasma capricolum recipient
cell to create new Mycoplasma mycoides cells that are
controlled only by the synthetic chromosome. The only
DNA in the cells is the designed synthetic DNA sequence,
including “watermark” sequences and other designed
gene deletions and polymorphisms, and mutations
acquired during the building process. The new cells have
expected phenotypic properties and are capable of
continuous self-replication.
Wednesday, May 19, 2010
RNAs en todos lados.
A series of reports over the last few years have indicated that a much larger portion of the mammalian genome is transcribed than can be accounted for by currently annotated genes, but the quantity and nature of these additional transcripts remains unclear. Here, we have used data from single- and paired-end RNA-Seq and tiling arrays to assess the quantity and composition of transcripts in PolyA+ RNA from human and mouse tissues. Relative to tiling arrays, RNA-Seq identifies many fewer transcribed regions (“seqfrags”) outside known exons and ncRNAs. Most nonexonic seqfrags are in introns, raising the possibility that they are fragments of pre-mRNAs. The chromosomal locations of the majority of intergenic seqfrags in RNA-Seq data are near known genes, consistent with alternative cleavage and polyadenylation site usage, promoter- and terminator-associated transcripts, or new alternative exons; indeed, reads that bridge splice sites identified 4,544 new exons, affecting 3,554 genes. Most of the remaining seqfrags correspond to either single reads that display characteristics of random sampling from a low-level background or several thousand small transcripts (median length = 111 bp) present at higher levels, which also tend to display sequence conservation and originate from regions with open chromatin. We conclude that, while there are bona fide new intergenic transcripts, their number and abundance is generally low in comparison to known exons, and the genome is not as pervasively transcribed as previously reported.
Citation: van Bakel H, Nislow C, Blencowe BJ, Hughes TR (2010) Most “Dark Matter” Transcripts Are Associated With Known Genes. PLoS Biol 8(5): e1000371. doi:10.1371/journal.pbio.1000371
Citation: van Bakel H, Nislow C, Blencowe BJ, Hughes TR (2010) Most “Dark Matter” Transcripts Are Associated With Known Genes. PLoS Biol 8(5): e1000371. doi:10.1371/journal.pbio.1000371
Tuesday, May 18, 2010
The DNA-binding landscape
GENE REGULATION
The DNA-binding landscape
Proteins or small molecules designed to bind certain DNA sequences and to regulate target genes have much promise in both basic and applied research. Aseem Ansari and colleagues at the University of Wisconsin, Madison, therefore tested the specificity of factor binding to DNA. They used custom DNA arrays displaying every possible 10-mer sequence—almost a half a million of them—to examine the binding profiles of engineered hairpin polyamides and protein transcription factors, as well as of several natural DNA-binding proteins, across sequence space. They quickly ran into a problem. The data were just too complex to understand intuitively. “We had this comprehensive binding dataset,” says Ansari, “and the first question was, how do you look at these data? If you use colors or tables or graphs to represent it, things begin to get very complicated very quickly.” They saw that protein transcription factors, in particular, bind fairly broadly across sequence space and that, although it is possible to extract a consensus binding motif, this often did not tell the whole story. What is more, the consequences of changing particular residues in a binding motif were not always simple or additive. So they had to find a new way of visualizing the data.
Nature Methods 7, 254 - 255 (2010)
doi:10.1038/nmeth0410-254a
Thursday, May 13, 2010
Systematic Comparison of Constitutive Promoters and the Doxycycline-Inducible Promoter
Constitutive promoters are used routinely to drive ectopic gene expression. Here, we carried out a systematic comparison of eight commonly used constitutive promoters (SV40, CMV, UBC, EF1A, PGK and CAGG for mammalian systems, and COPIA and ACT5C for Drosophila systems). We also included in the comparison the TRE promoter, which can be activated by the rtTA transcriptional activator in a doxycycline-inducible manner. To make our findings representative, we conducted the comparison in a variety of cell types derived from several species. We found that these promoters vary considerably from one another in their strength. Most promoters have fairly consistent strengths across different cell types, but the CMV promoter can vary considerably from cell type to cell type. At maximal induction, the TRE promoter is comparable to a strong constitutive promoter. These results should facilitate more rational choices of promoters in ectopic gene expression studies.
link
Constitutive promoters are used routinely to drive ectopic gene expression. Here, we carried out a systematic comparison of eight commonly used constitutive promoters (SV40, CMV, UBC, EF1A, PGK and CAGG for mammalian systems, and COPIA and ACT5C for Drosophila systems). We also included in the comparison the TRE promoter, which can be activated by the rtTA transcriptional activator in a doxycycline-inducible manner. To make our findings representative, we conducted the comparison in a variety of cell types derived from several species. We found that these promoters vary considerably from one another in their strength. Most promoters have fairly consistent strengths across different cell types, but the CMV promoter can vary considerably from cell type to cell type. At maximal induction, the TRE promoter is comparable to a strong constitutive promoter. These results should facilitate more rational choices of promoters in ectopic gene expression studies.
link
Thursday, May 06, 2010
Wednesday, April 14, 2010
International network of cancer genome projects
Nature 464, 993-998 (15 April 2010) doi:10.1038/nature08987
International Cancer Genome Consortium
The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Cancer remodeling in a basal-like breast cancer metastasis and xenograft.
Nature. April 15, 2010.
Genome remodelling in a basal-like breast cancer metastasis and xenograft
Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.
http://www.nature.com/nature/journal/v464/n7291/abs/nature08987.html
doi:10.1038/nature08989
Genome remodelling in a basal-like breast cancer metastasis and xenograft
Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.
http://www.nature.com/nature/journal/v464/n7291/abs/nature08987.html
doi:10.1038/nature08989
Wednesday, March 31, 2010
Transcriptome analyses of mouse and human mammary cell subpopulations reveals multiple conserved genes and pathways
Breast Cancer Research 2010, 12:R21doi:10.1186/bcr2560
| Published: | 26 March 2010 |
Introduction
Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step towards understanding pathways that regulate self-renewal, lineage commitment and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis, and compared with their normal human counterpart subsets in order to identify conserved genes and networks.
Methods
RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived, and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.
Results
The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, while the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, while IPA highlighted a number of conserved pathways in the three epithelial subsets.
Conclusions
The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in different models.
Friday, March 12, 2010
B-cell-derived lymphotoxin promotes castration-resistant prostate cancer.
Searched Keywords: Stat3, IKK, Microenvironment, Inflammation, Cancer
Nature. 2010 Mar 11;464(7286):302-5.
Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.
Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-kappaB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IkappaB kinase (IKK)-beta and its target NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-alpha, which stimulates metastasis by an NF-kappaB-independent, cell autonomous mechanism. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-beta activation results in production of cytokines that activate IKK-alpha and STAT3 in CaP cells to enhance hormone-free survival.
Wednesday, March 03, 2010
Do scientists really need a PhD?
Young scientists at a Chinese genomics institute are foregoing conventional postgraduate training for the chance to be part of major scientific initiatives. Is this the way of the future?
nature Vol 464 | Issue no. 7285 | 4 March 2010
www.nature.com/nature/journal/v464/n7285/pdf/464007a.pdf
nature Vol 464 | Issue no. 7285 | 4 March 2010
www.nature.com/nature/journal/v464/n7285/pdf/464007a.pdf
Wednesday, February 10, 2010
Method of the Year 2009, pluripotency
Nature Methods' Method of the Year 2009 goes to induced pluripotency for its potential for biological discovery. This series of articles—and the related video—showcase how induced pluripotency is coming into its own in 2009 as a tool for discovery in both basic and disease biology and explore the incredible impact this area promises to have in biological research.
January 2010, Volume 7 No 1 pp1-85
IAP Regulation of Metastasis
Cancer Cell, Volume 17, Issue 1, 53-64, 19 January 2010 | Copyright © 2010 Elsevier Inc. All rights reserved. | 10.1016/j.ccr.2009.11.021
Swarna Mehrotra, Lucia R. Languino, Christopher M. Raskett, Arthur M. Mercurio, Takehiko Dohi, Dario C. Altieri
* Highlights
* Inhibitor-of-Apoptosis (IAP) proteins mediate tumor cell invasion and metastasis
* This pathway requires NF-κB activation and is independent of IAP cytoprotection
* IAP tumor cell invasion involves signaling by fibronectin-β1 integrin and FAK, Src.
* Summary
* Inhibitor-of-Apoptosis (IAP) proteins contribute to tumor progression, but the requirements of this pathway are not understood. Here, we show that intermolecular cooperation between XIAP and survivin stimulates tumor cell invasion and promotes metastasis. This pathway is independent of IAP inhibition of cell death. Instead, a survivin-XIAP complex activates NF-κB, which in turn leads to increased fibronectin gene expression, signaling by β1 integrins, and activation of cell motility kinases FAK and Src. Therefore, IAPs are direct metastasis genes, and their antagonists could provide antimetastatic therapies in patients with cancer.
Thursday, February 04, 2010
Journal stem cell work 'blocked'
Journal stem cell work 'blocked'
| By Pallab Ghosh Science correspondent, BBC News |
 Billions of pounds of public money is spent on stem cell research |
Stem cell experts say they believe a small group of scientists is effectively vetoing high quality science from publication in journals.
In some cases they say it might be done to deliberately stifle research that is in competition with their own.
It has also emerged that 14 leading stem cell researchers have written an open letter to journal editors in order to highlight their dissatisfaction.
http://news.bbc.co.uk/2/hi/science/nature/8490291.stm
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