ONCOLOGY New Determinant of Human Breast Cancer Metastasis Discovered

Researchers at the University of Kentucky's Markey Cancer Center in Lexington, KY have provided new insight as to why the most severe subtype of breast cancer in humans frequently metastasizes. Tumor cells can exploit a cellular program that promotes cell migration and reduces adhesion between cells to spread to distant sites in the body (metastasis). This cellular program, known as the epithelial-mesenchymal transition, is normally restricted to wound healing, tissue remodeling and embryonic development. Increasing cell motility requires a decrease in E-cadherin, which functions to promote cell-cell adhesion. Led by Binhua Zhou, the research team identified G9a as a major repressor of E-cadherin expression. They found that G9a interacts with Snail, which can repress gene expression, to modify the E-cadherin promoter and block expression of the E-cadherin gene. Their findings establish that G9a is an important determinant of metastasis in the most severe sub-type of breast cancer, and suggest the development of new therapeutics targeting this pathway could potentially disrupt the metastatic disease.

TITLE: G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer

View this article at: http://www.jci.org/articles/view/57349?key=633f7fd0e6bf36bb229e

ONCOLOGY Limiting cancer caused by chronic viral infection

The Epstein-Barr virus has been linked to the development of several cancers of the immune system including Hodgkin's lymphoma and Burkitt lymphoma. However, this virus is also present in most healthy adults, suggesting that the cancer-promoting activity of the virus is normally constrained. Martin Allday and his colleagues at the Imperial College in London investigated a key viral gene, known as EBNA3B, to determine how it contributes to cancer development in a mouse model system. EBNA3B encodes a viral protein that can control the expression of several important human genes. The researchers mimicked Epstein-Barr viral infection in mice in the presence or absence of EBNA3B. They found that loss of EBNA3B promoted cancer, and in particular, B cell lymphomas. Importantly, they also found that some human B cell lymphomas patients had naturally occurring mutations in EBNA3B. The Allday team found that in mice, tumors without EBNA3B fail to trigger an immune response that might otherwise eliminate the tumor. These results help explain why the majority of the adult population can tolerate Epstein-Barr infection without developing lymphoma.

TITLE: EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors

View this article at: http://www.jci.org/articles/view/58092?key=7a7f0ed17d42e1d9af43

NEUROLOGICAL DISEASE Newly identified compound improves cognitive function in mouse model of Alzheimer's disease

Over 5 million Americans are living with Alzheimer's disease, an incurable type of dementia that is characterized by the abnormal accumulation of Aβ plaques in the brain. In this paper, Berislav Zlokovic and colleagues at the Zikha Neurogenetic Institute at the University of Southern California set out to identify new compounds that could potentially serve as effective therapy for Alzheimer's disease. In mouse models of Alzheimer's, a protein called RAGE (the receptor for advance glycation end products) mediates many of the clinical features of Alzheimer's, including Aβ protein circulation in the brain, inflammation and cognitive decline. The Zlokovic group discovered a novel compound (FPS-ZM1) that inhibits RAGE function and further tested the activity of this compound in a mouse model of Alzheimer's. They found this compound dramatically reduced Aβ levels and inflammation in the brain, and improved cognitive function in the mouse model system. These exciting preclinical data indicate that this compound merits further development as a potential therapeutic for Alzheimer's disease.

TITLE: A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease

View this article at: http://www.jci.org/articles/view/58642?key=636cba405c981453fc7a

CARDIOVASCULAR DISEASE Refining therapy for cardiovascular disease

Niacin, a supplement that has been shown to improve HDL or "good" cholesterol in patients, has generated interest as a potential therapy to improve cardiovascular health. However, niacin supplementation can be difficult for patients to tolerate due to facial flushing caused by excess production of prostaglandin D2. A study by Garret FitzGerald and colleagues at the University of Pennsylvania in Philadelphia sought to understand how niacin impacts prostaglandin D2 production in human platelets, and how blocking prostaglandin D2 activity might impact niacin's effects on cardiovascular health. The authors found in patients that niacin promotes the production prostaglandin D2 in platelets. Further, in mice they showed that the enzyme COX1 is responsible for platelet prostaglandin formation in response to niacin. These results may aid the understanding of the impacts of combined niacin therapy and inhibitors of prostaglandin D2 receptor.

TITLE: Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans

View this article at: http://www.jci.org/articles/view/59262?key=0908e2220edd411d0c2c

ONCOLOGY Multiple factors collide to spur cancer development

Cancer cells contain many genetic changes that allow uncontrolled cell division and growth. Researchers have long sought to better understand which mutations drive cancer development, and how multiple mutations collaborate to promote tumor growth. The RAS genes are among the most frequently mutated genes in cancer, and approximately 25% of all human cancers contain activating mutations in one of the RAS genes. Curiously, analysis of healthy human tissue samples shows the presence of a cancer-associated mutation in K-RAS in 10-20% of normal tissues, which indicates that K-RAS mutation alone does not cause cancer. In new research, Craig Logsdon and fellow researchers at the University of Texas MD Anderson Cancer Center in Houston sought to better understand what contributing factors are necessary to drive cancer in the presence of K-Ras mutation. Using a mouse model system, they found that chronic inflammation combined with expression of activated K-Ras promoted the development of precancerous lesions. Chronic inflammation is maintained by the activity of the NF-κB signaling pathway. After disrupting signaling through this pathway in mice, precancerous lesions were no longer observed, even in the presence of K-Ras mutation. These studies suggest that controlling inflammation in healthy adults with K-Ras mutation could potentially be an effective strategy for restraining cancer development in these individuals.

TITLE: An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice

View this article at: http://www.jci.org/articles/view/59743?key=ab54f55e6206fb93f017

IMMUNOLOGY Traffic stop: cue for B cell and T cell migration uncovered

The adaptive immune system provides a critical defense against pathogens in the body. Circulation of B cells and T cells allow the immune system to mount an effective attack on viruses and bacteria by specifically recognizing pieces of the invading pathogen as foreign. While the generation of B cells and T cells has been extensively studied, what triggers newly made B cells and T cells to enter circulation is incompletely understood. In this paper, Naoki Mochizuki and colleagues at the National Cerebral and Cardiovascular Center Research Institute in Osaka, Japan have now identified the cell type that generates a specific signal to stimulate the entry of B cells and T cells into circulation.

B cells and T cells develop in the bone marrow and thymus, respectively. Exit from these tissues is known to be promoted by the presence of shingosine-1 phosphate (S1P). Using knockout mice, the Mochizuki team showed that loss of Spn2, a transporter that controls production of the S1P, causes B cells to accumulate in bone marrow and T cells to accumulate in the thymus. They further showed that Spn2 was required specifically in endothelial cells, which form the lining of circulatory vessels, in order to promote normal B cell and T cell circulation. Thus, their study improves the understanding of the molecular mechanisms that control B cell and T cell trafficking. TITLE: The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice

View this article at: http://www.jci.org/articles/view/60746?key=52dcade2382bb68a0da2