JCI online early table of contents: Jan. 17, 2012

Some skin cancers, in particular basal cell carcinoma, can be successfully treated with a prescription cream containing the compound imiquimod. The antitumor effect of imiquimod is multifactorial. One of the more complex aspects of imiquimod's antitumor effects is its ability to modify the immune response. A team of researchers led by Maria Sibilia, at the Medical University of Vienna, Austria, has now identified a new way in which imiquimod modifies the immune system to clear tumors in a mouse model of melanoma, the most deadly form of skin cancer. Specifically, the team found that topical application of imiquimod leads to the recruitment of immune cells known as plasmacytoid DCs to the site of the tumor. Moreover, exposure to imiquimod at the site of the tumor then converts these cells into tumor-cell killers. Nina Bhardwaj and colleagues, at New York University, New York, discuss in an accompanying commentary the implications of these data for antitumor therapies designed to combat both skin cancers and other cancers.

TITLE: Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells

AUTHOR CONTACT:
Maria Sibilia
Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Phone: 43.1.4277.65131; Fax: 43.1.4277.65193; E-mail: maria.sibilia@meduniwien.ac.at.

View this article at: http://www.jci.org/articles/view/61034?key=bce90e43bcd605799561

ACCOMPANYING COMMENTARY
TITLE: Plasmacytoid dendritic cells lead the charge against tumors

AUTHOR CONTACT:
Nina Bhardwaj
The New York University Langone Medical Center and the New York University Cancer Institute, New York, New York, USA.
Phone: 212.263.5814; Fax: 212.263.6729; E-mail: Nina.Bhardwaj@med.nyu.edu.

View this article at: http://www.jci.org/articles/view/61345?key=3f09068264890ed311f8

Infection with hepatitis B virus (HBV) is a major health problem worldwide, despite the fact that a highly effective preventative vaccine exists. A modified form of the immune molecule IFN-alpha is commonly used to treat individuals infected with HBV. The rationale behind this is that IFN-alpha inhibits HBV replication in vivo and in vitro, although the mechanisms by which it does this have not been clearly defined. A team of researchers — led by Maura Dandri, at University Medical Hospital Hamburg-Eppendorf, Germany; and Massimo Levrero, at Sapienza University, Italy — has now identified a new mechanism by which IFN-alpha suppresses HBV replication in vitro and in vivo. The authors hope that this new insight could help in the development of new approaches to treat individuals infected with HBV.

TITLE: IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome

AUTHOR CONTACT:
Maura Dandri
University Medical Hospital Hamburg-Eppendorf, Hamburg, Germany.
Phone: 49.40.741052949; Fax: 49.40.741057232; E-mail: m.dandri@uke.de.

Massimo Levrero
Sapienza University, Rome, Italy.
Phone: 39.06.49970892; Fax: 39.06.4452388; E-mail: massimo.levrero@uniroma1.it.

View this article at: http://www.jci.org/articles/view/58847?key=3a5c4549350a2300311e

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third leading cause of cancer-related death worldwide. In most cases, HCC develops after a sustained period of inflammation in the liver, for example as a result of alcoholism or infection with hepatitis C virus. Genetic mutations that activate the signaling molecule beta-catenin are seen in a subset of HCCs, and individuals with these tumors have a better prognosis. A team of researchers, led by Mireille Viguier and Christine Perret, at the Institut Cochin, Paris, has now generated data in mice that provide a potential molecular explanation for this.

Viguier, Perret, and colleagues found that activation of beta-catenin signaling modulates the inflammatory environment to control tumor development. Specifically, beta-catenin signaling was shown to activate both pro- and anti-inflammatory molecules. The resulting inflammatory environment, while permissive for tumor development also contained components that somewhat restrained tumor development and spread to distant sites. Detailed analysis of these restraining components identified potential new targets for immunotherapeutic approaches to treating patients with HCC.

TITLE: Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice

AUTHOR CONTACT:
Mireille Viguier
Institut Cochin, INSERM U1016, UMR CNRS 8104, Université René Descartes, Paris, France.
Phone: 33.1.57.27.80.06; Fax: 33.1.57.27.80.87; E-mail: mireille.viguier@inserm.fr.

Christine Perret
Institut Cochin, INSERM U1016, UMR CNRS 8104, Université René Descartes, Paris, France.
Phone: 33.1.44.41.25.64; Fax: 33.1.44.41.24.21; E-mail: christine.perret@inserm.fr.

View this article at: http://www.jci.org/articles/view/43937?key=745e8aa8846e5f104b79

A central function of our kidneys is to filter waste from our blood and to divert it into our urine. Specialized cells known as podocytes are key to the integrity of the filtration barrier. Many kidney diseases are characterized by abnormal function of the filtration barrier, which occurs because podocyte morphology (structure) is altered. Such diseases are known as glomerular diseases. A team of researchers led by Lawrence Holzman, at the University of Pennsylvania, Philadelphia, has now identified a molecular pathway involved in the alterations to podocyte morphology observed in mouse models of glomerular disease. They team suggest that inhibitors of molecules in this signaling pathway, for example inhibitors of the FAK-Cas-Crk protein complex, might help prevent the podocyte structural changes associated with glomerular diseases.

TITLE: Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease

AUTHOR CONTACT:
Lawrence B. Holzman
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.573.1831; Fax: 215.898.1830; E-mail: lholzman@upenn.edu.

View this article at: http://www.jci.org/articles/view/60070?key=26e460af554f691c1702