Public Release:  JCI table of contents: Nov. 20, 2008

Journal of Clinical Investigation

EDITOR'S PICK: Preventing tumor cells from refueling: a new anticancer approach?

New data, generated in mice, by Pierre Sonveaux and colleagues, at Université catholique de Louvain, Belgium, have identified a potential new target for anticancer therapeutics.

Not all cells in a tumor are equal, for example, some are in regions rich in oxygen, whereas others are in regions deprived of oxygen (hypoxic regions). It had been thought that the tumor cells in these two regions used the same type of fuel to generate energy, specifically glucose. However, Sonveaux and colleagues have now shown that although hypoxic tumor cells use glucose to generate energy, well-oxygenated tumor cells use a different fuel, lactate. Further, the lactate used by the well-oxygenated tumor cells as a fuel was released from the hypoxic tumor cells as a waste product of the chemical reactions that burned glucose to generate energy, leading the authors to suggest that the different tumor cells exist in symbiosis.

More detailed analysis revealed that well-oxygenated cells took up lactate via the protein MCT1 and that inhibiting MCT1 made the well-oxygenated cells switch to using glucose as a fuel to generate energy. This disrupted the symbiotic relationship between the hypoxic and well-oxygenated tumor cells and in two mouse models of cancer led to decreased tumor growth, as the hypoxic tumor cells became deprived of glucose, and rendered the remaining cells sensitive to irradiation. As MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, the authors suggest that MCT1 is a potential new target for anticancer therapeutics. In an accompanying commentary, Greg Semenza, at Johns Hopkins University School of Medicine, Baltimore, discusses this concept further as well as other therapeutic implications.

TITLE: Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Pierre Sonveaux
Université catholique de Louvain, Brussels, Belgium.
Phone: 32-2-764-52-67; Fax: 32-2-764-52-69; E-mail:

Mary Jane Gore
Senior Science Writer
Duke Medicine News and Communications, Duke University, Durham, North Carolina, USA.
Phone: (919) 660-1309 (office), (919) 323-0179 (cell); E-mail:

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TITLE: Tumor metabolism: cancer cells give and take lactate

Gregg L. Semenza
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Fax: (443) 287-5618; E-mail:

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EDITOR'S PICK: To contract or not: a key question for the uterine muscles in pregnancy

During pregnancy, the muscles of the uterus are relatively inactive. A switch to an activated state capable of strong contractions is therefore essential prior to the onset of labor. Kathleen Martin and colleagues, at Dartmouth Medical School, Lebanon, have now provided new insight into the events that prime the uterine muscles for contraction, something that they hope might have implications for the development of therapies for preterm labor (i.e., labor that occurs before 37 weeks of pregnancy), the most serious complication of pregnancy in developed countries.

In the study, when the protein IP on the surface of muscle cells in human uterine tissue strips obtained from pregnant women undergoing Caesarean delivery prior to the onset of natural labor was stimulated by agonist chemicals, it induced the upregulation of proteins involved in muscle contraction. Further, the same chemicals increased the contraction of these tissue strips in response to the hormone oxytocin. The authors therefore conclude that the molecule that normally binds IP in vivo, prostacyclin, primes the muscles in the human uterus, allowing for strong contractions during labor. As Michael Taggart, at Newcastle University, United Kingdom, and colleagues discuss in an accompanying commentary, these data might be viewed by many as contentious, because prostacyclin is a smooth muscle relaxant. However, they do provide an explanation for the paradoxical observation that one of the major signaling molecules produced by the uterus just prior to labor is prostacyclin.

TITLE: Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

Kathleen A. Martin
Dartmouth Medical School, Lebanon, New Hampshire, USA.
Phone: (603) 650-7439; Fax: (603) 650-4928; E-mail:

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TITLE: Possible dual roles for prostacyclin in human pregnancy and labor

Michael J. Taggart
Newcastle University, Newcastle upon Tyne, United Kingdom.
Phone: 44-191-222-6988; Fax: 44-191-222-5066; E-mail:

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REPRODUCTIVE BIOLOGY: Helping the embryo implant: a new role for one type of immune cell

One of the most critical stages in establishing a pregnancy is the implantation of the embryo in the wall of the uterus. Although the accumulation of immune cells known as DCs has been observed in the uterus after fertilization and prior to implantation, their function was not known. However, Steffen Jung and colleagues, at The Weizmann Institute of Science, Israel, have now discovered that mouse uterine DCs are crucial for implantation and that they function to ensure that new blood vessels form in the wall of the uterus; they do not function by dampening immune responses to the embryo, as had been anticipated.

The authors used mice engineered such that they could be depleted of all their DCs (including those in the uterus) by administration of a toxin. Depletion of DCs in both normal mice and mice lacking the ability to mount an immune response resulted in a severe defect in implantation, indicating that uterine DCs had a role in implantation that was independent of their effects on the immune system. Further analysis revealed that this role was to produce two factors (sFlt1 and TGF-beta-1) critical for coordinating blood vessel formation. The importance of this work and the implications for understanding potential causes of human infertility where implantation is impaired as well as other pregnancy related complications (for example, preeclampsia) are discussed by both the authors and, in an accompanying commentary, Jeffrey Pollard, at Albert Einstein College of Medicine, New York.

TITLE: Uterine DCs are crucial for decidua formation during embryo implantation in mice

Steffen Jung
The Weizmann Institute of Science, Rehovot, Israel.
Phone: 972-8-9342787; Fax: 972-8-9342787; E-mail:

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TITLE: Uterine DCs are essential for pregnancy

Jeffrey W. Pollard
Albert Einstein College of Medicine, New York, New York, USA.
Phone: (718) 430-2090; Fax: (718) 430-8972; E-mail:

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PULMONARY: Hormones: the reason why females with cystic fibrosis have a worse outlook than males with the disease

Females with cystic fibrosis have more severe disease than males with cystic fibrosis and have a shorter lifespan. Although many suggestions have been put forward to explain this sex-related difference, a concrete mechanism to explain it has remained elusive. However, Robert Tarran and colleagues, at University of North Carolina, Chapel Hill, have now uncovered a molecular mechanism whereby the hormone estrogen has a negative impact on the clearance of mucus from the lungs; the buildup of mucus in the lung is a hallmark of cystic fibrosis and serves as a focus for severe infections. As the estrogen antagonist tamoxifen blocked one aspect of the molecular mechanism in vitro, the authors suggest that antiestrogens might be beneficial in the treatment of cystic fibrosis.

In an accompanying commentary, Pamela Zeitlin, at Johns Hopkins School of Medicine, Baltimore, outlines the complexities of the molecular mechanism uncovered by Tarran and colleagues, and further discusses the clinical implications of the data.

TITLE: 17beta-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia

Robert Tarran
University of North Carolina, Chapel Hill, North Carolina, USA.
Phone: (919) 966-7052; Fax: (919) 966-5178; E-mail:

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TITLE: Cystic fibrosis and estrogens: a perfect storm

Pamela L. Zeitlin
Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 955-2035; Fax: (410) 955-1030; E-mail:

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ONCOLOGY: The tumor environment determines whether the cellular process autophagy enables cancer cells to live or die

Confusingly, the cellular process autophagy (essentially self-eating) has been implicated in both cancer cell death and survival. New insight into this paradox has now been provided by the work of Robert Bast Jr. and colleagues, at the University of Texas MD Anderson Cancer Center, Houston, which indicates that the context in which the process occurs determines the outcome.

Expression of the gene ARHI is lost or downregulated in most cases of ovarian cancer. In the study, in vitro re-expression of ARHI in multiple human ovarian cancer cell lines induced autophagy and cell death. However, when one of these cells lines was transplanted into mice as a xenograft, multiple factors within the tumor environment turned ARHI-induced autophagy into a mechanism of tumor cell survival, leading to tumor dormancy. In addition to providing insight into the paradox that autophagy is associated with both cancer cell death and survival, the authors suggest that the data might provide new therapeutic approaches for the treatment of cancer. Ravi Amaravadi, at the University of Pennsylvania, Philadelphia, discusses this further in an accompanying commentary.

TITLE: The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells

Robert C. Bast Jr.
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 792-7743; Fax: (713) 745-2107; E-mail:

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TITLE: Autophagy-induced tumor dormancy in ovarian cancer

Ravi K. Amaravadi
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 662-7402; Fax: (215) 662-7865; E-mail:

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CARDIOLOGY: Increased calcium sensitivity in the heart can make for an irregular heartbeat

New mouse studies, by Björn C. Knollmann and colleagues, at Vanderbilt Medical Center, Nashville, have uncovered a potential new molecular mechanism to explain why some individuals suffer irregular heartbeats that can cause sudden death. The results suggest a potential new target for drugs that would be beneficial to those at risk.

Sudden cardiac death caused by irregular heartbeats (cardiac arrhythmias) is responsible for 10% of all deaths in the US. In some individuals anatomical abnormalities in the heart (such as hypertrophic cardiomyopathy, a disease of the muscle of the heart characterized by a portion of the muscle being thickened) increase the risk of irregular heartbeats and sudden death. In the study, mice expressing mutant forms of the protein troponin T that cause hypertrophic cardiomyopathy in humans were found to have an increased risk of irregular heartbeats. Detailed analysis indicated that the enhanced susceptibility to irregular heartbeats was a result of increased sensitivity of a key component of the heart contractile units (specifically the myofilaments) to Ca2+. As the drug blebbistatin, which decreases the sensitivity of myofilaments to Ca2+, provided the mice with substantial protection from irregular heartbeats, the authors suggest that normalizing myofilament Ca2+sensitivity in individuals with hypertrophic cardiomyopathy might help protect them from irregular heartbeats and sudden death.

In an accompanying commentary, Céline Fiset and Wayne R. Giles provide insight into the complexities of the new data, highlighting their significance.

TITLE: Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice

Björn C. Knollmann
Vanderbilt Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
Phone: (615) 343-6493; Fax: (615) 343-4522; E-mail:

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TITLE: Cardiac troponin T mutations promote life-threatening arrhythmias

Wayne R. Giles
University of Calgary, Calgary, Alberta, Canada.
Phone: (403) 220-5607; Fax: (403) 220-0448; E-mail:

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