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JCI online early table of contents: June 6, 2011

JCI Journals

EDITOR'S PICK: Immune cells link pregnancy and tumor spread

Individuals with cancer often do not die as a result of their initial tumor but as a result of tumors at distant sites that are derived from the initial tumor. Pregnancy is a condition that seems to be permissive for tumor dissemination, as breast tumors arising during pregnancy display a tendency for early spread to distant sites (metastasis). Research in mice, led by Ivan Stamenkovic, at the University of Lausanne, Switzerland, has now uncovered a possible reason for this.

Stamenkovic and colleagues found that the increased metastasis from tumors of several different types that they observed in pregnant mice was a result of decreased activity of immune cells known as NK cells. Furthermore, at least part of the inhibitory effect on NK cells was mediated by another group of immune cells, myeloid-derived suppressor cells. Consistent with this, the gene expression profile of the lungs of pregnant mice (a site to which many of the tumors metastasized) was reflective of myeloid-derived suppressor cell accumulation. Of clinical interest, the majority of genes downregulated in the lungs of pregnant mice were also expressed at lower levels in samples from lung cancer patients with poor prognosis than in samples from patients with better prognosis. The authors therefore suggest that myeloid-derived suppressor cells may represent a shared mechanism of immune suppression during pregnancy and tumor growth.

TITLE: Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

Ivan Stamenkovic
Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Phone: 41.21.314.7136; Fax: 41.21.314.7110; E-mail:

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HEMATOLOGY: Breaking down blood clots to beat DVT

Deep vein thrombosis (DVT) is a serious medical condition in which a blood clot (also known as a thrombus) forms in one or more of the deep veins in the body, usually those in the legs. DVT can result in death if part of the blood clot breaks off and ends up blocking the major arterial blood vessels in the lungs. New research in a mouse model of DVT, led by Toshikazu Kondo, at Wakayama Medical University, Japan, has now determined that the soluble factor IFN-gamma acts to slow down thrombus resolution and defined a mechanism by which it does this. As administration of a biological molecule that neutralized IFN-gamma accelerated thrombus resolution in normal mice, Kondo and colleagues suggest that IFN-gamma might be a good therapeutic target for the acceleration of thrombus resolution in individuals with DVT.

TITLE: Absence of IFN-gamma accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice

Toshikazu Kondo
Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
Phone: 81.73.441.0641; Fax: 81.73.441.0641; E-mail:

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TUMOR IMMUNOLOGY: Virus lends a hand to eradicate tumors

Intensive research efforts are being focused on developing immune-based anticancer therapies. One approach that has been developed is to vaccinate patients with immune cells known as DCs treated in such a way that they carry tumor cell proteins. However, the efficacy of this approach in the clinic has thus far been modest. A team of researchers, led by Stefan Kubicka and Florian Kühnel, at Hannover Medical School, Germany, has now identified a way to enhance the effectiveness of DC-based cancer immunotherapy in mice. The team hopes that their approach can be translated to the clinic.

The idea behind DC-based anticancer immunotherapy is that the DCs present fragments of tumor protein to a subset of immune cells known as CD8+ T cells, specifically those that recognize the tumor protein fragments, triggering them to attack and destroy the tumor. Kubicka, Kühnel, and colleagues found that if they injected a virus into the mouse's tumor alongside their DC-based therapy then the mouse generated potent antiviral CD8+ T cell responses. This combinatorial approach, which they named oncolysis-assisted DC vaccination (ODC), caused marked regression of tumors and led to the successful eradication of secondary tumors in the lungs that had not been injected with virus, which is essential if metastatic cancers (i.e., cancers that have spread to distant sites) are to be treated using this approach. Thus, the authors suggest that ODC might provide a way to improve the clinical efficacy of DC-based anticancer immunotherapy.

TITLE: Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice

Stefan Kubicka
Hannover Medical School, Hannover, Germany.
Phone: 49511.532.6766; Fax: 49511.532.4896; E-mail:

Florian Kühnel
Hannover Medical School, Hannover, Germany.
Phone: 49511.532.6766; Fax: 49511.532.4896; E-mail:

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CARDIOVASCULAR DISEASE: A miR reduction in atherosclerosis

High levels of "good" cholesterol (HDL-cholesterol) are associated with a decreased risk of atherosclerosis -- a disease of the major arterial blood vessels that is one of the major causes of heart attack and stroke. This suggests that therapeutics that increase HDL levels could be clinically useful. However, better understanding of the mechanisms regulating HDL levels is needed if the potential of HDL-raising therapeutic strategies is to be realized. Recent data indicate that the RNA molecule miR-33 indirectly lowers HDL levels, leading to the hypothesis that targeting this miR-33 might be atheroprotective. A team of researchers, led by Kathryn Moore, at New York University School of Medicine, New York, has now shown in mice that this is the case and defined the underlying mechanism. The team therefore suggests that miR-33 antagonism might provide a promising strategy to treat individuals with atherosclerosis.

TITLE: Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis

Kathryn J. Moore
New York University School of Medicine, New York, New York, USA.
Phone: 212.263.9259; Fax: 212.263.9115; E-mail:

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PULMONARY: Fibroblasts key to dangerous remodeling of the airways

Chronic obstructive pulmonary disease (COPD) and chronic asthma are two of the most common lung diseases. In both diseases, the airways become obstructed, in part as a result of airway remodeling, a term that encompasses substantial changes in the cellular constituency of the walls of the airway that cause scarring and inflammation. A team of researchers, led by Jody Lynn Baron and Stephen Nishimura, at the University of California at San Francisco, San Francisco, has now determined that cells known as fibroblasts regulate both airway scarring and inflammation in mouse models that mimic the airway remodeling that occurs in COPD and chronic asthma. Furthermore, these effects of the fibroblasts were dependent on them expressing the molecules integrin alpha-v-beta-8 and TGF-beta. The team therefore suggests that inhibiting integrin alpha-v-beta-8-mediated TGF-beta activation by lung fibroblasts could provide a new way to prevent airway remodeling in both COPD and chronic asthma.

TITLE: Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin alpha-v-beta-8-mediated activation of TGF-beta

Jody Lynn Baron
University of California at San Francisco, San Francisco, California, USA.
Phone: 415.476.5728; Fax: 415.476.0659; E-mail:

Stephen L. Nishimura
University of California at San Francisco, San Francisco, California, USA.
Phone: 415.206.5906; Fax: 415.206.5988; E-mail:

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CARDIOLOGY: Pinpointing a new role for regulating gene expression in heart disease

Research performed in mice, by Adam Stein, Gregory Dressler, and colleagues, at the University of Michigan, Ann Arbor, has provided new insight into the mechanisms that control gene expression in adult heart cells. Importantly, they find that perturbation of these mechanisms can cause heart defects, suggesting that these mechanisms might be clinically relevant.

To prevent the more than 1 meter of DNA in our cells from becoming tangled, it is wound around protein complexes known as histones. Histones also play a role in regulating the expression of genes contained within the DNA that they organize. As such, the expression of a gene can be modulated by the presence or absence of modifications to certain histone building blocks. For example, methylation of building block K4 of histone H3 (H3K4) promotes gene expression. Stein, Dressler, and colleagues set out to investigate the importance of H3K4 methylation to gene expression in adult heart muscle cells by generating mice in which they could ablate a key component of the protein responsible for adding the methylation modification to H3K4. Decreased H3K4 methylation was found to alter the gene expression profile of adult mouse heart muscle cells. One gene that was downregulated was Kcnip2, a gene known to be downregulated in the hearts of patients with heart failure. Consistent with this, the mice were more likely to develop an irregular heart beat after injection with isoproterenol (an agonist of certain nerve cells) and caffeine. The authors therefore suggest that changes in histone modification may underlie clinically relevant heart diseases.

TITLE: Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes

Adam B. Stein
University of Michigan, Ann Arbor, Michigan, USA.
Phone: 734.764.6528; Fax: 734.615.3326; E-mail:

Gregory R. Dressler
University of Michigan, Ann Arbor, Michigan, USA.
Phone: 734.764.6528; Fax: 734.763.2162; E-mail:

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IMMUNOLOGY: The protein LRF helps immune cells grow up

Immune cells known as B cells have a key role in defending the body from invading microbes. A team of researchers, led by Takahiro Maeda, at the Beckman Research Institute of City of Hope, Duarte, has now determined in mice that the gene regulatory protein LRF has a key role in the development and function of mature B cells.

Interestingly, the ability of LRF to regulate mature B cell development and function was found to be dependent on it dimerizing. However, downstream of this event, it regulated mature B cell development and function by distinct mechanisms. As knocking down expression of LRF was found to be toxic to human B cell lymphoma cell lines, Maeda and colleagues suggest that disrupting LRF dimers could provide a new approach to treating B cell cancers and autoimmune diseases, both of which arise as a result of dysregulation of B cell maturation.

TITLE: The LRF transcription factor regulates mature B cell development and the germinal center response in mice

Takahiro Maeda
Beckman Research Institute of City of Hope, Duarte, California, USA.
Phone: 626.359.8111, ext. 68824; Fax: 626.301.8973; E-mail:

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