JCI table of contents: June 7, 2007

Radiation is used to treat a variety of tumors and the response of tumors to radiation is dependent on endothelial cell death, which in turn limits oxygen delivery to the tumor, causing hypoxia and tumor cell death. Recently, radiation-induced hypoxia was shown to trigger tumor resistance to radiation via the activation of new blood vessel formation (angiogenesis) through molecules known as HIF-1–regulated cytokines. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, Claire Magnon and colleagues from Institut Gustave Roussy, France, show that a combination of radiation treatment and the use of angiogenesis inhibitors such as canstatin is able to overcome HIF-1–dependent tumor survival pathways and increases tumor cell death. The authors found that following application of this dual therapy to mice, HIF-1alpha increased the activity of the canstatin-induced tumor apoptotic pathway, which lead to lethal tumor damage. The study demonstrates a crucial role for angiogenesis inhibitors in shifting tumor radioresistance towards tumor apoptosis and suggests that a combination of radiation and angiogenesis inhibitors could potentially be used to overcome HIF-1–dependent tumor radioresistance.

TITLE: Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1alpha–mediated tumor apoptotic switch

AUTHOR CONTACT:
Claire Magnon
Mount Sinai School of Medicine, New York, New York, USA.
E-mail: claire.magnon@mssm.edu or clairemagnon@free.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=30269

Physicians currently use many variables to estimate the probability of prostate cancer recurrence following surgical removal of the whole or part of the prostate gland. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, a team of researchers led by Michael Donovan at Aureon Laboratories report their development of a novel model for the improved prediction of prostate cancer recurrence. The authors examined many clinical variables in more than 300 patients and used multidisciplinary methodology they term “systems pathology” in order to develop their predictive model. They applied their predictive model to a separate cohort of patients and showed that the model can successfully predict prostate cancer recurrence (defined by rising serum levels of prostate-specific antigen) with 82% predictive accuracy, 96% sensitivity, and 72% specificity. This model has broad applications for the diagnosis, treatment management, and prediction of recurrence of prostate cancer.

TITLE: Improved prediction of prostate cancer recurrence through systems pathology

AUTHOR CONTACT:
Michael J. Donovan
Aureon Laboratories Inc., Yonkers, New York, USA.
Phone: (914) 377-4037; Fax: (914) 377-4001; Email: Michael.Donovan@aureon.com

View the PDF of this article at: https://www.the-jci.org/article.php?id=31399

Inflammatory bowel disease, which includes Crohn’s disease and ulcerative colitis, involves both immune and nonimmune cells. Previous studies have established that the vasculature of the gut mucosa is an important nonimmune component of intestinal inflammation and that the protein C (PC) signaling pathway is an important checkpoint in the inflammatory process. Endothelial protein C receptor (EPCR) and thrombomodulin (TM) are expressed at high levels in the resting microvasculature and they convert PC into its active, anti-inflammatory form. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, Silvia Danese and colleagues from Istituto di Ricovero e Cura a Carattere Scientifico in Rozzano, Italy, show that in Crohn’s disease and ulcerative colitis there is a loss of EPCR and TM expression by endothelial cells that line the intestine, which results in impaired PC activation by the inflamed mucosal microvasculature. The authors went on to show that administration of recombinant, activated PC to human intestinal endothelial cells had a potent anti-inflammatory effect and reversed experimental colitis. The results of the study suggest that that PC pathway is crucially involved in regulating intestinal inflammation triggered by changes in the mucosal microvasculature. Restoring the PC pathway may therefore represent a potential therapeutic approach to suppressing intestinal inflammation in inflammatory bowel disease.

TITLE: Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease

AUTHOR CONTACT:
Silvio Danese
Istituto di Ricovero e Cura a Carattere Scientifico, Rozzano, Italy.
Phone : 39-3392318230; Fax : 39-0282244590; E-mail : sdanese@hotmail.com

View the PDF of this article at: https://www.the-jci.org/article.php?id=31027

Iron is essential for red blood cell production and delivery of oxygen to the body’s tissues, and its supply is tightly regulated by hepcidin – a small peptide expressed by the liver. Hepcidin upregulation, which may occur in response to cancer or infection, blocks iron export from cells via the only known iron exporter – ferroportin – as hepcidin binding to ferroportin causes ferroportin internalization and degradation. This block in iron export results in a condition known as the anemia of chronic disease. Conversely, hepcidin downregulation is associated with increased iron plasma levels and the iron overload disorder hemochromatosis. In order to compensate for these imbalances, hepcidin expression is increased by iron overload and decreased by anemia, however the mechanisms that govern hepcidin’s response to these stimuli are not completely known. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, Randall Johnson and colleagues from University of California, San Diego, establish that the von Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway provides an essential link between iron balance and hepcidin regulation. They show that, in mice, anemia causes a drop in oxygen availability to tissues, which in turn leads to decreased VHL-mediated degradation of HIF-alpha. The increased HIF-alpha activity suppresses hepcidin expression, causing increased ferroportin levels and serum iron availability, in turn allowing increased red blood cell production. The data suggest that inhibition of VHL could represent a novel approach for the treatment of anemia of chronic disease.

TITLE: Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)

AUTHOR CONTACT:
Randall S. Johnson
University of California, San Diego, La Jolla, California, USA.
Phone : (858) 822-0509; Fax: (858) 822-5833; E-mail: rsjohnson@ucsd.edu

Victor Nizet
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 534-7408; Fax: (858) 534-5611: Email: vnizet@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31370

The enzyme endothelial nitric oxide synthase (eNOS) plays a vital role in blood vessel function. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, Paul Huang and colleagues from Massachusetts General Hospital show that modulation of the serine amino acid residue at position 1179 in eNOS, the site at which eNOS undergoes phosphorylation, affects vascular function and recovery from stroke in mice. The authors found that transgenic mice expressing a form of eNOS that could be phosphorylated developed less severe strokes and had improved cerebral blood flow in a model of stroke compared to mice expressing a form of eNOS that was not able to be phosphorylated. The data indicate that modulation of the S1179 phosphorylation site affects vasodilation and cerebral blood flow and that these effects determine outcome in a mouse model of stroke.

TITLE: The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo

AUTHOR CONTACT:
Paul L. Huang
Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Phone : (617) 724-9849; Fax: (617) 726-5806; E-mail: phuang1@partners.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=29877

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in immunity and tumor development has remained unclear: mice deficient in GM-CSF have been shown to be sensitive to bacterial infection and prone to tumors, yet the persistent expression of GM-CSF has been shown to cause tumor cell invasion and spread to other locations. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, Glenn Dranoff and colleagues from Dana-Farber Cancer Institute explored the mechanisms underlying the physiological as well as pathophysiological effects of GM-CSF.

One mechanism by which GM-CSF promotes immune tolerance is by modulating the ability of macrophages to clear apoptotic cells, which leads to the production of immune suppressing cytokines. In the current study, the authors show that GM-CSF–mediated uptake of apoptotic cells by antigen-presenting cells (APCs) is itself mediated by the expression of milk fat globule EGF 8 (MFG-E8) on APCs. This uptake also triggers the production of regulatory T cells and Th1 cells that are critical to the regulation of the host immune response to tumors. The data demonstrate how GM-CFS–induced MFG-E8 expression mediates immune tolerance, which has potentially significant implications for cancer immunotherapy.

TITLE: MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and anti-inflammatory activities of GM-CSF

AUTHOR CONTACT:
Glenn Dranoff
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone : (617) 632-5051; Fax: (617) 632-5167; E-mail: glenn_dranoff@dfci.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=30966