JCI online early table of contents: Oct. 5, 2009
EDITOR'S PICK: Mutated FGFR4 protein helps a childhood cancer spread
Rhabdomyosarcoma (RMS) is a childhood cancer thought to originate from skeletal muscle. In patients whose disease has spread (metastasized) from the initial tumor site the chance of long-term survival is poor. Hopes for a therapy for such patients are not high, as little is known about the factors that control tumor progression and metastasis. However, Javed Khan and colleagues, at the National Cancer Institute, Bethesda, have now determined that the protein FGFR4 has a role in RMS progression and have data suggesting that it might be a good drug target for the treatment of individuals with RMS.
In the study, higher levels of expression of the FGFR4 gene were found to be associated with advanced-stage cancer and poor survival. Conversely, reducing FGFR4 expression in a human RMS cell line decreased its ability to grow and metastasize when transplanted into mice. Further analysis identified mutations in the FGFR4 gene in 7.5% of human RMS tumor samples analyzed. When two of the FGFR4 mutants generated by these genetic mutations were analyzed further, they were found to be constitutively activated forms of FGFR4 that increased the proliferative, invasive, and metastatic capacities of a murine RMS cell line. Importantly, treatment with a pharmacologic inhibitor of FGFRs made the murine RMS cells expressing the FGFR4 mutants very susceptible to death, leading the authors to suggest that targeting FGFR4 might be of therapeutic benefit in RMS.
TITLE: Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models
AUTHOR CONTACT:
Javed Khan
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 435-2937; Fax: (301) 480-0314; E-mail: khanjav@mail.nih.gov.
View this article at: http://www.jci.org/articles/view/39703?key=140858eba01ab916a067
EDITOR'S PICK: Iron regulates the TLR4 inflammatory signaling pathway
Iron is a micronutrient essential to the survival of both humans and disease-causing microbes. Changes in iron levels therefore affect the severity of infectious diseases. For example, individuals with mutations in their HFE gene have exceedingly high levels of iron in their liver and are more susceptible to infection with a number of microbes. Exactly how changes in iron levels affect susceptibility to infectious disease has not been clearly determined, although it has been observed that mice lacking Hfe mount an impaired inflammatory response following oral infection with the bacterium that causes salmonella.
Bobby Cherayil and colleagues, at Massachusetts General Hospital, Charlestown, have now defined a molecular mechanism underlying the impaired inflammatory response to oral infection with the bacterium that causes salmonella in mice lacking Hfe. Specifically, these mice have low levels of free iron in immune cells known as macrophages and this impairs signaling along a pathway required for sensing the presence of bacteria such as the one that causes salmonella and triggering an inflammatory response (the TLR4/TRAM/TRIF pathway). As drugs that mimic the altered iron distribution associated with Hfe deficiency reduced intestinal damage associated with infection with the salmonella-causing bacterium and reduced intestinal damage in a noninfectious inflammatory situation, the authors suggest that local manipulation of iron levels might provide a new approach to controlling inflammation.
TITLE: Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice
AUTHOR CONTACT:
Bobby J. Cherayil
Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Phone: (617) 726-4170; Fax: (617) 726-4172; E-mail: cherayil@helix.mgh.harvard.edu.
View this article at: http://www.jci.org/articles/view/39939?key=4fae98a76d788644e09d
HEMATOLOGY: Brain cells help stimulate production of new red blood cells
TITLE: The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice
AUTHOR CONTACT:
Randall S. Johnson
University of California at San Diego, La Jolla, California, USA.
Phone: (858) 822-0509; Fax: (858) 822-5833; E-mail: rsjohnson@ucsd.edu.
View this article at: http://www.jci.org/articles/view/39378?key=51a04c36dc93a5459302
PULMONARY: New targets for treating acute lung injury caused by a blood transfusion?
TITLE: Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury
AUTHOR CONTACT:
Mark R. Looney
University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 476-9190; Fax: (415) 502-2126; E-mail: mark.looney@ucsf.edu.
View this article at: http://www.jci.org/articles/view/38432?key=6068e31c5b040516c8d4
ONCOLOGY: New role for the protein Sema3A as an inhibitor of blood vessel formation and tumor growth
TITLE: Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models
AUTHOR CONTACT:
Enrico Giraudo
Institute for Cancer Research and Treatment, University of Torino School of Medicine, Turin, Italy.
Phone: 39-011-9933505; Fax: 39-011-9933524; E-mail: enrico.giraudo@ircc.it.
View this article at: http://www.jci.org/articles/view/36308?key=205fd206ca6b4a17a400
TUMOR IMMUNOLOGY: Understanding what keeps the immune system from attacking colorectal cancer
TITLE: Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma
AUTHOR CONTACT:
Philipp Beckhove
The German Cancer Research Center, Heidelberg, Germany.
Phone: 49-6221-423745; Fax: 49-6221-423702; E-mail: p.beckhove@dkfz.de.
View this article at: http://www.jci.org/articles/view/39608?key=8a17b039dc645369a55c
Source: Journal of Clinical Investigation
