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JCI online early table of contents: January 4, 2009

EDITOR'S PICK: Depleting breast cancerinitiating cells by targeting the protein CXCR1

Recent data suggest that many types of cancer, including breast cancer, are initiated and maintained by a rare population of cells within the tumor known as cancer stem cells. These cells are thought also to contribute to tumor spread (metastasis) and recurrence after treatment, meaning that many researchers are seeking to develop approaches to target them. A team of researchers, at the University of Michigan Comprehensive Cancer Center, Ann Arbor, and U891/Inserm/Institut Paoli-Calmettes, France, has now identified a strategy to target human breast cancer stem cells that decreased tumor growth and metastasis in mice xenotransplanted with human breast cancer cells.

The team, led by Max Wicha and Christophe Ginestier, found that inhibiting the cell surface protein CXCR1, with either an antibody or a small molecule known as repertaxin, selectively depleted the cancer stem cell population in two human breast cancer cell lines in vitro. Loss of the cancer stem cells was followed by extensive death of many of the remaining tumor cells. Importantly, treatment with repertaxin had similar effects in mice xenotransplanted with human breast cancer cells: cancer stem cells were selectively depleted leading to a reduction in tumor growth and metastasis. The authors therefore suggest that strategies that target CXCR1, the soluble protein that binds to it, and the signaling pathways downstream of it might provide a good approach to deplete breast cancer stem cells and prove beneficial to women with breast cancer.

TITLE: CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Max S. Wicha
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Phone: (734) 647-9923; Fax: (734) 647-9480; E-mail:

Christophe Ginestier
Centre de Recherche en Cancrologie de Marseille, U891/Inserm/Institut Paoli-Calmettes, Marseille, France.
Phone: 33-4-91-22-35-09; Fax: 33-4-91-22-35-44; E-mail:

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EDITOR'S PICK: How to build bone: separate bone formation from bone destruction

Treatments for osteoporosis (a disease characterized by reduced bone density, which leads to an increased risk of fracture) need to increase the amount and/or quality of bone. As bone formation is tightly coupled to bone destruction, researchers looking to develop new approaches to build bone in individuals with osteoporosis need to identify ways to separate the two processes. Natalie Sims and colleagues, at St. Vincent's Institute, Melbourne, Australia, have now identified one way to do this in mice.

In the study, the molecule oncostatin M (OSM) was found to induce distinct functions in mice upon binding to two different cell surface proteins. When OSM bound OSMR it stimulated the production of cells that destroy bone. Consistent with this, mice lacking OSMR were found to have increased bone density. However, when OSM bound LIFR it blocked production of a protein that inhibits bone formation. Importantly, OSM acting via LIFR did not stimulate the production of cells that destroy bone. These data indicate the existence of a pathway by which bone formation can be stimulated independently of bone destruction.

TITLE: Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

Natalie A. Sims
St. Vincent's Institute, Melbourne, Victoria, Australia.
Phone: 613-9288-2555; Fax: 613-9416-2676; E-mail:

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IMMUNOLOGY: Dampening CD4+ immune cell function via the protein TLR4

The immune system uses a large number of proteins to sense the presence of microbes, including a family of proteins known as TLRs. The function of TLRs on immune cells known as DCs and macrophages has been well characterized, but the role of TLR4 on immune cells known as CD4+ T cells has not been determined. However, Jos M. Gonzlez-Navajas, Eyal Raz and colleagues, at the University of California at San Diego, La Jolla, have now determined that triggering TLR4 on CD4+ T cells dampens their inflammatory function, as TLR4 deficiency in two mouse models of colitis (inflammation of the intestines) accelerated the development of disease and/or induced more severe disease. Further analysis identified a molecular signaling pathway underlying the inhibitory effects of TLR4 triggering on CD4+ T cell inflammatory function, providing insight into the regulation of CD4+ T cell responses.

TITLE: TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

Jos M. Gonzlez-Navajas
The University of California at San Diego, La Jolla, California, USA.
Phone: (858) 534-5380; Fax: (858) 534-0409; E-mail:

Eyal Raz
The University of California at San Diego, La Jolla, California, USA.
Phone: (858) 534-5444; Fax: (858) 534-0409; E-mail:

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CARDIOLOGY: It's good to talk: changing how nerves communicate in congestive heart failure

A team of researchers, led by Keiichi Fukuda, at Keio University School of Medicine, Tokyo, Japan, has now determined in rodents how congestive heart failure triggers substantive changes to the nerves that control heart function.

Heart function is controlled by both the sympathetic nervous system and the parasympathetic nervous system. In congestive heart failure, increased activation of the sympathetic nervous system causes damage to the heart muscle, a decline in heart function, and potentially lethal abnormal heartbeats. In the study, failing rat heart muscle cells were found to secrete molecules known as gp130-signaling cytokines that caused sympathetic nerves to change the molecule that they used to communicate from norepinephrine to acetylcholine. The clinical significance of these observations in rodents was highlighted by the fact that the sympathetic nervous system in the heart of patients with congestive heart failure showed evidence of the same switch to reliance on acetylcholine for communication.

TITLE: Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents

Keiichi Fukuda
Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Phone: 81-3-5363-3874; Fax: 81-3-5363-3875; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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