JCI online early table of contents: April 1, 2011

(Press-News.org) EDITOR'S PICK Cat's out of the bag: PUMA contributes to ulcerative colitis

Ulcerative colitis (UC) is an inflammatory bowel disease thought to be related to aberrant activation of the immune system in the intestine. Recent research has also suggested that regulated cell death (apoptosis) of the intestinal epithelial cells is a contributing factor to the pathogenesis. However, the molecular mechanisms that control the cellular response to inflammation are incompletely understood. In this paper, Lin Zhang, at the University of Pittsburgh, in Pennsylvania, found that in mice, a protein called PUMA (p53 upregulated modulator of apoptosis) was responsible for inducing apoptosis in the intestinal epithelium in response to inflammation; the absence of PUMA inhibited the inflammation-induced death of intestinal epithelial cells and development of colitis. PUMA levels were also increased in the diseased tissues of UC patients. The researchers are hopeful that PUMA could represent a promising target for the development of new UC therapies.

TITLE: PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

AUTHOR CONTACT:
Lin Zhang
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Phone: 412-623-1009; Fax: 412-623-7778; E-mail: zhanglx@upmc.edu View this article at: http://www.jci.org/articles/view/42917?key=0975eddb1bfd896d7140

EDITOR'S PICK Gag order: how DNA silencing can promote cancer

Cells control which genes they express by multiple mechanisms, one of which is the direct modification of DNA with small molecules. Methylation of genes effectively silences them, and excess DNA methylation, particularly of genes that control the cell cycle, is known to promote cancer formation. However, it is unclear whether the enzymes that modify DNA in this way target specific genes or whether random modifications select cells for enhanced tumorigenic capacity. In new research, Rudolf Jaenisch and colleagues, at the Whitehead Institute in Cambridge, Massachusetts, investigated DNA methylation in a mouse model of colon cancer. They found that a DNA methylating enzyme, Dnmt3b, targeted specific genes for silencing, and that these genes were similar to those silenced in human tumors. In addition, the researchers believe that their results show that aberrant DNA methylation may be one of the initiating events in the development of cancer.

TITLE: Genes methylated by DNA methyltransferase 3b are similar in mouse intestine and human colon cancer

AUTHOR CONTACT:
Rudolf Jaenisch
Whitehead Inst. For Biomedical Rsch., Cambridge, MA, USA
Phone: 617/258-5186; Fax: 617-258-6505; E-mail: jaenisch@wi.mit.edu View this article at: http://www.jci.org/articles/view/43169?key=18e46da07945967b6b41

METABOLISM New insight into the development of insulin resistance

Muscles, liver, and other tissues take up sugar from the blood stream in response to the hormone insulin. Insulin resistance, which is associated with obesity, is a condition in which tissues stop responding to the insulin signal, often leading to diabetes and cardiovascular disease. Insulin resistance in the muscle is thought to be related to exposure to saturated fatty acids, which are converted to molecules called ceramides that can inhibit insulin signaling. Saturated fatty acids are also known to activate inflammatory signaling through a pathway that uses the receptor Toll-like Receptor 4 (Tlr4), and inflammation is known to be required for lipid-induced insulin resistance. In this paper, Scott Summers and colleagues, of Duke University- NUS, in Singapore, investigated the connection between Tlr4 signaling and ceramides in the development of insulin resistance in mice. They found that Tlr4 signaling promoted ceramide synthesis, and that this was required for saturated fatty acids to induce insulin resistance. The researchers believe that this finding helps explain the mechanism of insulin resistance, and may help identify new therapeutic targets for the disorder.

TITLE: Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

AUTHOR CONTACT:
Scott Summers
Duke-NUS Graduate Medical School, Singapore
Phone: (65) 6516-8793; Fax: (65) 6534-8632; E-mail: scott.summers@duke-nus.edu.sg View this article at: http://www.jci.org/articles/view/43378?key=13423d10b959bb6ea300

GASTROENTEROLOGY Molecule may connect colon inflammation and cancer

Ulcerative colitis (UC) is an inflammatory bowel disease that puts patients at high risk for developing colon cancer, but the mechanism that explains the link between the two diseases is not completely understood. The enzyme heparanase is overexpressed in most human cancers, and functions to modulate the interaction of tumor cells with the extracellular environment, promoting a number of events that allow cancer progression. Patients with UC have been shown to have high levels of heparanase in their colon, but whether this enzyme plays a role in the pathogenesis of UC or its progression to cancer is unknown. In this paper, Israel Vlodavsky and colleagues, at The Rappaport Faculty of Medicine, in Haifa, Israel and the Hadassah-Hebrew University Medical Center in Jerusalem, Israel, investigated a mouse model of UC-associated cancer. They found that heparanase activated immune cells to help maintain a state of chronic inflammation in the gut, and to promote continued expression of the enzyme. Heparanase also created an environment that was conducive to tumor growth. The researchers believe that their findings suggest that heparanse is an attractive therapeutic for the treatment of UC and the prevention of colon cancer.

TITLE: Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice

AUTHOR CONTACT:
Israel Vlodavsky
Rappaport Faculty of Medicine and Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Phone: +972-2-6776776; Fax: +972-2-642-2794; E-mail: vlodavsk@cc.huji.ac.il View this article at: http://www.jci.org/articles/view/43792?key=291ed98052881d743e35

ONCOLOGY New mechanism identified in gastric cancer

Gastric cancer is one of the leading causes of cancer-related deaths. Infection with H. pylori bacteria has been identified as the major risk factor for gastric cancer, but the molecular pathogenesis has not been completely defined. The specific activation of the NF‐kB pathway promotes formation of inflammation‐associated tumors including gastric cancer, but the action of NF‐kB in gastric carcinomas is not completely understood. Expression of TFF1- a peptide found in the epithelial cells of the stomach- is lost in the majority of human gastric cancers. In this paper, Wael El‐Rifai and colleagues, at Vanderbilt University in Nashville, Tennessee, investigated the relationship between TFF1 expression and the NF‐kB in gastric cancer pathogenesis. They found that TFF1 normally suppresses NF-kB-mediated inflammation, and that TFF1 loss leads to activation of NF‐kB and tumor formation in mice. The researchers believe that these results help define the sequence of events in gastric cancer progression, and explain the connection between TFF1 loss and the inflammation that leads to cancer development.

TITLE: Loss of TFF1 is associated with activation of NF-κB–mediated inflammation and gastric neoplasia in mice and humans

AUTHOR CONTACT:
Wael El-Rifai
Vanderbilt University Medical Center, Nashville, TN, USA
Phone: 615-322 7934; Fax: ; E-mail: wael.el-rifai@vanderbilt.edu View this article at: http://www.jci.org/articles/view/43922?key=f275eda2c8f0ecd54fa7

ONCOLOGY Hope for chemotherapy-resistant tumors?

As tumors grow, the cells in the interior experience a reduction in oxygen availability; in response, levels of hypoxia inducible factor-1 (HIF1) are increased. Elevated HIF-1 is known to make tumor cells more resistant to chemotherapy and to increase the likelihood of metastasis, but the underlying mechanism of HIF-induced chemoresistance is poorly understood. Dual specificity phosphatases (DUSPs) are negative regulators of an intracellular signaling pathway. In new research, Shaw-Jenq Tsai and colleagues, of National Cheng Kung University in Taiwan, found that DUSP2 expression is lost in many tumors, and that this effect is due to transcriptional repression by HIF. Furthermore, they found that loss of DUSP2 is directly related to the increased chemoresistance that results from increased HIF-1 expression. The researchers believe that their findings identify DUSP2 as a critical link between hypoxia and tumor progression, and suggest that it might represent a promising new therapeutic target.

TITLE: Suppression of dual specificity phosphatase-2 by hypoxia increases chemoresistance and cancer malignancy in humans and mice

AUTHOR CONTACT:
Shaw-Jenq Tsai
National Cheng Kung University Medical College, Taiwan
Phone: +886-6-2353535 Ext. 5426; Fax: +886-6-236-2780; E-mail: seantsai@mail.ncku.edu.tw View this article at: http://www.jci.org/articles/view/44362?key=7d24c941a96bda2fab38

VASCULAR BIOLOGY Three genes, two mechanisms, one disease: understanding cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are vascular disorders that result in bleeding in the central nervous system, and can lead to stroke and neurological deficits. Three genes have been linked to familial cases of CCM, in each, patients are found to have loss of function of one copy of the gene (heterozygosity). Although two of these genes, called Krit1 and Ccm2, are known to function in development of the heart and blood vessels, the function of the third gene, called Pdcd10, is unknown. The molecular mechanisms that result in CCM formation are not completely understood, and currently no medical therapy is available for these patients. In this paper, Dean Li and colleagues, at the University of Utah in Salt Lake City, investigated the role of Pdcd10 in CCM formation by generating a mouse model in which the gene could be conditionally deleted. They found that Pdcd10 affects different signaling pathways than Krit1 and Ccm2, though mutations in all three result in similar pathological malformations. In addition, they found that CCMs were initiated when mice lost function of both copies of any of these three genes- a condition called loss of heterozygosity. The researchers believe that these findings suggest that effective treatment will require the identification of causative mutations in each CCM patient.

TITLE: Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice

AUTHOR CONTACT:
Dean Li
University of Utah, Salt Lake City, UT, USA
Phone: 801-585-5505; Fax: ; E-mail: dean.li@u2m2.utah.edu View this article at: http://www.jci.org/articles/view/44393?key=55c5c28f183dbff49268

IMMUNOLOGY Insight into the intestinal immune system

The intestine is colonized by bacteria that may help promote healthy digestion (called commensals) and also by species that can be pathogenic. Thus, it is important that the immune system differentiate between these two, so that inflammatory responses to invading species may be controlled. A great deal of the immune system is dedicated to this function, indeed, the majority of antibody-producing B cells are found in the gut. However, little is known about how these antibodies are created, or their specificity. In this paper, Hedda Wardemann and colleagues, at the Max Planck Institute in Berlin, Germany, investigated the antigens to which these intestinal-resident B cells react in samples taken from human patients. They found that the majority of these B cells produce antibodies directed against single antigens, which suggests that they arose from specific immune responses to intestinal bacteria. Importantly, the researchers believe that these findings help us understand the dysregulated immune responses that occur in patients with inflammatory bowel disease.

TITLE: The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

AUTHOR CONTACT:
Hedda Wardemann
Max Planck Institute for Infection Biology, Berlin, Germany
Phone: +49 30 28460 360; Fax: ; E-mail: wardemann@mpiib-berlin.mpg.de View this article at: http://www.jci.org/articles/view/44447?key=6e47478ebd2a56e1bb5f

ONCOLOGY Innovative strategy to improve cancer therapy

As solid tumors grow, they require new blood vessels to maintain their supply of oxygen and nutrients. Thus, vascular disrupting agents (VDAs) have been investigated as potential therapies, and have been shown to promote the regression of tumors in humans and in mouse models. However, the blood vessels that remain at the periphery after treatment can re-grow and re-vascularize the tumor, limiting the clinical efficacy of VDA treatment. Tumor associated macrophages, particularly those that express the receptor TIE-2 (TEMs), are a highly pro-angiogenic cell type, and infiltration of TEMs following chemotherapy is correlated with tumor re-vascularization and relapse. In this paper, Claire Lewis and colleagues, of the University of Sheffield Medical School, in Sheffield, UK, found that in a mouse model of breast cancer, treatment with a VDA promoted the recruitment of TEMs. Inhibiting TEM recruitment or diminishing this cell population in mice markedly improved the response to VDA treatment. The researchers believe that this study suggests that pharmacologically targeting the TEM population may improve the therapeutic efficacy of VDAs in solid tumor treatment.

TITLE: TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice

AUTHOR CONTACT:
Claire Lewis
University of Sheffield Medical School, Sheffield, GBR
Phone: 44-114-2903; Fax: 44-114-278-0059; E-mail: claire.lewis@sheffield.ac.uk View this article at: http://www.jci.org/articles/view/44562?key=0ebc588869c547909fc6

GASTROENTEROLOGY New target in the prevention of colitis and colon cancer

Colorectal cancer (CRC) is one of the most common malignancies; although not all of the causes are known, there is a well-established link between chronic inflammation, as occurs in cases of ulcerative colitis, and the development of CRC. One of the proteins up-regulated in intestinal inflammation is called CD98; this protein is thought to contribute to control of signaling pathways that regulate cell division, survival, and other functions. Interestingly, CD98 is upregulated in many human carcinomas, but it is unclear what role it plays in the pathogenesis of cancer. In new research, a group led by Hang Thi Thu Nguyen, at Emory University in Atlanta, Georgia, investigated the role of CD98 in CRC using mouse models in which the molecule could be overexpressed or deleted specifically in the intestine. They found that over-expression of CD98 promoted cell proliferation and the production of pro-inflammatory molecules, thus increasing the inflammatory responses and promoting colitis-associated tumorgenesis. Conversely, deleting CD98 made mice resistant to inflammation-induced CRC. The researchers believe that their findings show that CD98 could be a therapeutic target for the treatment and prevention of intestinal inflammation and CRC.

TITLE: CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

AUTHOR CONTACT:
Hang Thi Thu Nguyen
Emory University, Atlanta, GA, USA
Phone: 404-727-6246; Fax: 404-727-5767; E-mail: hnguye9@emory.edu View this article at: http://www.jci.org/articles/view/44631?key=37aa6f35e748a4bdba92

PULMONARY BIOLOGY Pathway that worsens lung cancer severity identified

Lung cancer is one of the most common and deadly forms of cancer. Cigarette smoking has been identified as one of the major causes of the disease, but lung cancers can arise in non-smokers, and research suggests that mutations in cell signaling pathways underlie these events. Aberrant signaling of the Wnt/β catenin pathway has been implicated in the pathogenesis of many malignancies including colon cancer, but the role of this pathway in lung cancer has not been established.

In this paper, Edward Morrissey and colleagues at the University of Pennsylvania, in Philadelphia, investigated the role of Wnt/β catenin signaling in the development of lung cancer in mice. They found that activating the pathway did not by itself induce tumor formation, but did increase the frequency and size of tumors induced by mutations in a second oncogene. The researchers believe that their findings suggest that Wnt/β catenin activation is a marker of more aggressive lung cancer, and hope that this may help clinicians more accurately diagnose and treat the human disease.

TITLE: Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium

AUTHOR CONTACT:
Edward Morrisey
University of Pennsylvania, Philadelphia, PA, USA
Phone: 215-573-3010; Fax: 215-573-2094; E-mail: emorrise@mail.med.upenn.edu View this article at: http://www.jci.org/articles/view/44871?key=419c8a1e94b1f81e5eb0

BACTERIOLOGY Small changes can have big effects on bacterial virulence

Infection with a given bacterial species can have dramatically variable effects, depending on the strain. Group A streptococci (GAS), for example, can cause pneumonia, flesh-eating bacterial syndrome, or a simple colonization that is symptom free. This variation is thought to be related to slight changes in the DNA sequence of the bacteria, so called single nucleotide polymorphisms (SNPs), that alter the functions of the proteins that the bacteria produces. However, the role of these SNPs in pathogenesis is incompletely understood.

Analysis of the genome of a GAS strain previously demonstrated that SNPs were very frequent in a gene called RopB, which in turn is known to regulate an important GAS virulence factor. In this paper, James Musser and colleagues, of the Methodist Hospital Research Institute in Houston, Texas, investigated the effects of SNPs within RopB on strain virulence by sequencing the gene in many different strains. They found that single amino acid changes within RopB could markedly alter global gene expression patterns and alter strain virulence. They believe that this helps to explain how a small genome change within a species can affect the virulence of a given strain. The researchers hope that their method could be adapted to the study of other bacterial pathogens, and could provide insight to guide the development of novel therapeutics.

TITLE: Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence

AUTHOR CONTACT:
James Musser
The Methodist Hospital Research Institute, Houston, TX, USA
Phone: 713-441-5890; Fax: 713-441-3447; E-mail: jmmusser@tmhs.org View this article at: http://www.jci.org/articles/view/45169?key=08b7c4d6419273b3e908

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