News Release

JCI online early table of contents: March 1, 2012

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: Potential new therapeutic target for a subset of aggressive breast cancers

The main cause of death in women with breast cancer is spread of the original tumor to distant sites, a process known as metastasis. New therapeutic targets are urgently needed. A team of researchers led by Stefan Offermanns and Thomas Worzfeld, at the Max-Planck-Institute for Heart and Lung Research, Germany, has now generated data in mice and humans that suggest that the protein Plexin-B1 represents a new candidate therapeutic target to treat patients with breast cancer found to overexpress the molecule ErbB-2.

ErbB-2 is overexpressed in approximately 30% of all breast cancers, and ErbB-2–overexpressing tumors have high metastatic potential and poor prognosis. Offermanns, Worzfeld, and colleagues found that overexpression of ErbB-2 in human breast cancer cell lines led to activation of Plexin-B1, and that this promoted human breast cancer cells to develop in vitro characteristics of metastatic cells. Moreover, in a mouse model of ErbB-2–overexpressing breast cancer, ablation of Plexin-B1 reduced the occurrence of metastases, while in human patients with ErbB-2–overexpressing breast cancer, low levels of Plexin-B1 expression correlated with better prognosis. Offermanns, Worzfeld, and colleagues therefore suggest that blocking the ErbB-2/Plexin-B1 interaction or inhibiting Plexin-B1–mediated signaling might reduce the risk of metastasis in patients with breast cancer overexpressing ErbB-2.

TITLE: ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

AUTHOR CONTACT:
Stefan Offermanns
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Phone: 49-6032-705-1201; Fax: 49-6032-705-1204; E-mail:
stefan.offermanns@mpi-bn.mpg.de.

Thomas Worzfeld
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Phone: 49-6032-705-1213; Fax: 49-6032-705-1204; E-mail:
thomas.worzfeld@mpi-bn.mpg.de.

View this article at: http://www.jci.org/articles/view/60568?key=5d15b60e11a0b3362f65

EDITOR'S PICK: Sensitizing tumor cells to radiotherapy

Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. Tumor resistance to radio- and/or chemotherapy remains a significant clinical problem. A team of researchers led by Nils Cordes, at Dresden University of Technology, Germany, has now identified a way to enhance the sensitivity of human HNSCC cell lines to radiation such that their growth is delayed in xenografted mice.

In the study, Cordes and colleagues determined that a beta-1 integrin/FAK/cortactin signaling pathway is crucial for HNSCC resistance to radiotherapy. Inhibiting beta-1 integrin sensitized HNSCC cells to radiotherapy and delayed tumor growth in xenografted mice. Thus, Cordes and colleagues suggest that targeting beta-1 integrin could be used in combination with radiotherapy and radiochemotherapy to increase the survival of patients with HNSCC.

TITLE: Beta-1 integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy

AUTHOR CONTACT:
Nils Cordes
Dresden University of Technology, Dresden, Germany.
Phone: 49-351-458-7401; Fax: 49-351-458-7311; E-mail: Nils.Cordes@OncoRay.de

View this article at: http://www.jci.org/articles/view/61350?key=7ca2ac820f5d245efcc0

ONCOLOGY: New insight into brain tumor aggressiveness

Malignant gliomas are the most common and lethal of all human brain tumors that originate in the brain. Patients with malignant gliomas have a poor prognosis because it is a highly aggressive form of cancer that is commonly resistant to current therapies. New therapeutic approaches are much needed, but deeper understanding of the mechanisms underlying malignant glioma aggressiveness is needed if they are to be developed. In this context, a team of researchers led by Erwin Van Meir, at Emory University, Atlanta, has gained new insight into how the protein P14ARF — expression of which is lost in 60%󈞼% of malignant gliomas — suppresses tumor development and progression. Specifically, they find that P14ARF inhibits malignant glioma–induced formation of new blood vessels that bring in nutrients required for tumor growth. Van Meir and colleagues therefore suggest that restoring P14ARF activity or targeting molecules that function in the pathway downstream of P14ARF to inhibit blood vessel formation could provide a new approach to block the growth of malignant gliomas and potentially other tumors.

TITLE: P14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3

AUTHOR CONTACT:
Erwin G. Van Meir
Emory University, Atlanta, Georgia, USA.
Phone: 404-778-5563; Fax: 404-778-5550; E-mail: evanmei@emory.edu.

View this article at: http://www.jci.org/articles/view/38596?key=7beeb4e23ccc74350b3e

BACTERIOLOGY: Unraveling the chain of events leading to virulence determinant activity

Persistent infection with Helicobacter pylori, a bacterium that can be found colonizing the stomach lining of almost half the world's population, increases an individual's risk of developing stomach cancer. Individuals infected with Helicobacter pylori strains carrying the virulence determinant CagA are at substantially greater risk of developing stomach cancer than those that harbor CagA-negative strains. This suggests that CagA has an important role in cancer initiation and development. Many of the functions of CagA require it to be phosphorylated by proteins in the host cell. A team of researchers led by Steffen Backert, at University College Dublin, Ireland, has now shed light on the phosphorylation process, revealing it to be a tightly regulated and coordinated sequential process. The data also provide insight into how differential phosphorylation patterns affect CagA function and lead Anne Müller, at the University of Zürich, Switzerland, to suggest in an accompanying commentary that detailed analysis of CagA phosphorylation status could help determine a Helicobacter pylori–infected individual's level of risk of developing stomach cancer.

TITLE: c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains

AUTHOR CONTACT:
Steffen Backert
University College Dublin, Dublin, Ireland.
Phone: 353-1-716-2155; Fax: 353-1-716-1183; E-mail: steffen.backert@ucd.ie.

View this article at: http://www.jci.org/articles/view/61143?key=05d7a989d0fb9e6ac91f

ACCOMPANYING COMMENTARY
TITLE: Multistep activation of the Helicobacter pylori effector CagA

AUTHOR CONTACT:
Anne Müller
Institute of Molecular Cancer Research, University of Zürich, Zürich,
Switzerland.
Phone: 41-44-635-3474; Fax: 41-44-635-3484; E-mail: mueller@imcr.uzh.ch.

View this article at: http://www.jci.org/articles/view/61578?key=95ade54944224b05ef08

IMMUNOLOGY: Stairway to T cell development found in the human tonsil

Central to the effective functioning of the immune system is the presence of a broad repertoire of immune cells known as T cells, which develop in an organ known as the thymus. There is some evidence to suggest that T cells can also develop in tissues other than the thymus, but no complete program of human T cell development has been described in an extrathymic tissue. Now, a team of researchers led by Michael Caligiuri, at The Ohio State University, Columbus, has uncovered clear evidence that a stepwise program of T cell development occurs outside the thymus within the human tonsil. Although it is not clear how significant a contribution T cell development in the tonsil makes to generating the T cell repertoire in healthy individuals, Caligiuri and colleagues suggest that it might be important in the setting of poor thymic function or congenital deficit and in the context of autoimmunity, cancer, or regenerative medicine.

TITLE: Evidence for a stepwise program of extrathymic T cell development within the human tonsil

AUTHOR CONTACT:
Michael A. Caligiuri
The Ohio State University, Columbus, Ohio, USA.
Phone: 614-293-7521; Fax: 614-293-3132; E-mail:
Michael.Caligiuri@osumc.edu.

View this article at: http://www.jci.org/articles/view/46125?key=f22c42a5fd52764465f0

HEPATOLOGY: Understanding how acetaminophen kills liver cells

Overdoses of acetaminophen (also known as paracetamol) account for most drug overdoses in a number of countries, including the United States. Such overdoses damage the liver, causing acute liver failure, which can be fatal. A team of researchers led by Hartmut Jaeschke, at the University of Kansas Medical Center, Kansas City, has now provided new insight into the mechanisms by which acetaminophen causes liver damage in mice and humans. Specifically, they find that in liver cells, acetaminophen damages the cellular compartments that generate power (mitochondria) and causes the DNA in the nucleus to fragment, leading to cell death by a process known as necrosis. These data are important, as it had previously been suggested that acetaminophen-induced liver cell toxicity was a result of cellular events that lead to an alternative cell death process known as apoptosis.

TITLE: The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation

AUTHOR CONTACT:
Hartmut Jaeschke
University of Kansas Medical Center, Kansas City, Kansas, USA.
Phone: 913-588-7969; Fax: 913-588-7501; E-mail: hjaeschke@kumc.edu.

View this article at: http://www.jci.org/articles/view/59755?key=50f5172399a45b6295df

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