JCI early table of contents for March 12, 2012

The liver is unique among mammalian organs in its ability to regenerate after significant tissue damage or even partial surgical removal. Laurie DeLeve and her colleagues at the University of Southern California in Los Angeles wanted to better understand which cells are specifically responsible for driving liver regeneration. A specialized cell type, known as liver sinusoidal endothelial cells, has generally been thought to promote regeneration of liver tissue. However, the DeLeve team suspected that stem cells and progenitor cells, which have the capacity to differentiate into mature cell types, might be responsible for stimulating liver regeneration by generating hepatocyte growth factor. Using a rat model system, they first identified the presence of stem and progenitor cells that give rise to liver sinusoidal endothelial cells in both the liver and the bone marrow. They next sought to determine which population of stem and progenitor cells are required for regeneration. DeLeve and colleagues found that the bone marrow-derived cells were not required for liver cell proliferation in the absence of damage. In contrast, following surgical removal of a portion of the rat liver, an infusion of bone marrow-derived progenitor cells was required for liver regeneration. These results improve our understanding of how liver tissue can regenerate following damage and may shed light on liver complications in patients with suppressed bone marrow tissue.

TITLE:
Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats

AUTHOR CONTACT:
Laurie D. DeLeve
University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Phone: 323-442-3248; Fax: 323-442-3238; E-mail: deleve@usc.edu

View this article at: http://www.jci.org/articles/view/58789?key=21e2857b21106f232595

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

AUTHOR CONTACT:
Binhua Zhou
University of Kentucky College of Medicine, Lexington, KY, USA
Phone: 859-323-4474; E-mail: peter.zhou@uky.edu

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

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

AUTHOR CONTACT:
Martin Allday

Imperial College London, London, GBR
Phone: 44 (0)2075943836; E-mail: m.allday@imperial.ac.uk
View this article at: http://www.jci.org/articles/view/58092?key=7a7f0ed17d42e1d9af43

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

AUTHOR CONTACT:
Berislav Zlokovic
Keck School of Medicine - University of Southern California, Los Angeles, CA, USA
Phone: 585-273-3131; Fax: 585-273-3133; E-mail: berislav_zlokovic@urmc.rochester.edu
View this article at: http://www.jci.org/articles/view/58642?key=636cba405c981453fc7a

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

AUTHOR CONTACT:
Garret FitzGerald
School of Medicine University of Pennsylvania, Philadelphia, USA
Phone: 215-898-1185; E-mail: garret@spirit.gcrc.upenn.edu

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

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

AUTHOR CONTACT:
Craig Logsdon
University of Texas, Houston, TX, USA
Phone: (713) 563-3585; E-mail: clogsdon@mdanderson.org
View this article at: http://www.jci.org/articles/view/59743?key=ab54f55e6206fb93f017

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

AUTHOR CONTACT:
Naoki Mochizuki
Natl. Cerebr. and Cardiovasc. Ctr. Res. Inst, Osaka, JPN
Phone: 81-6-6833-5012; Fax: 81-6-6835-5461; E-mail: nmochizu@ri.ncvc.go.jp
View this article at: http://www.jci.org/articles/view/60746?key=52dcade2382bb68a0da2

Patients who die of cancer frequently die from cancer that has spread from the original tumor site to other parts of the body (metastasis). Unfortunately, the majority of metastatic cancers have limited effective treatment options and what triggers metastasis is still poorly understood. A team of researchers led by Dan Theodorescu at the University of Colorado Comprehensive Cancer Center sought to better understand why bladder cancer metastases frequently appear in lung. They found that an inflammatory response in lung triggers a microenvironment that supports tumor metastasis.

Theodorescu and colleagues demonstrated that the signaling protein RhoGDI2 decreases expression of an extracellular matrix protein known as versican, and that high versican expression in bladder tumors is associated with poor patient survival. Using a mouse model system, they showed that versican promotes inflammation in the lung by infiltration of immune cells known as macrophages and that versican was required for lung metastasis. Their study suggests that future therapies which promote RhoGDI2 activity might discourage the tumor microenvironment which favors metastatic bladder cancer.

TITLE:
RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration

AUTHOR CONTACT:
Dan Theodorescu
University of Colorado Denver, Aurora, CO, USA
Phone: 303-724-7135; E-mail: dan.theodorescu@ucdenver.edu
View this article at: http://www.jci.org/articles/view/61392?key=1d742b4f66012a2d73cb