September 2004
Journal of Clinical Investigation
JCI table of contents: 1 September, 2004EDITOR'S CHOICE:
Zoledronic Acid Zings Cervical Cancer
Cervical cancer is the second most common cancer among women worldwide. Research has shown that progression of the pre-malignant stages to invasive cervical cancer is associated with the onset of new blood vessel growth called angiogenesis. Using a mouse model of cervical cancer to explore the molecular control of angiogenesis in cancer progression, Douglas Hanahan and colleagues, from the University of California, San Francisco, found that a drug called zoledronic acid was able to halt the progression of cervical cancer in these mice. The researchers first showed that cervical cancers in this mouse model had several characteristics similar to human cervical cancer. They further found that an important player in cervical cancer progression was an enzyme called matrix metalloprotease-9, which stimulated angiogenesis. The researchers treated these mice with bisphosphonate, zoledronic acid, a matrix metalloprotease inhibitor that is already FDA-approved for treatment of patients with bone metastases. Zoledronic acid treatment in the mouse model impaired angiogenesis and slowed cervical tumor progression and growth. The researchers showed that this drug acted by both decreasing matrix metalloprotease-9 gene expression and inhibiting the activity of any remaining matrix metalloprotease-9 protein. This study provides evidence that an already approved drug, zoledronic acid, may be useful for therapy in cervical cancer and other diseases resultant from matrix metalloprotease-9 expression and activity.
TITLE: An amino-bisphosphonate targets MMP-9�expressing macrophages and angiogenesis to impair cervical carcinogenesis
AUTHOR CONTACT:
Douglas Hanahan
University of California, San Francisco, 513 Parnassus Avenue San Francisco, CA 94143, USA
Phone: 415-476-9209; Fax: 415-731-3612; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/22087.pdf
Stopping Skin Cancer -- Stat3
Human cancers generally develop through several steps -- initiation, promotion, and progression -- which require the accumulation of between 4 to 6 genetic mutations. Skin cancer is the most common cancer for both men and women. John DiGiovanni and colleagues, at The University of Texas MD Anderson Cancer Center, now show that a protein called Stat3 is required for skin cancer initiation and promotion. Stat3 is a protein that normally acts to regulate the expression several genes in the cell. Stat3, when it is improperly activated, is known to be involved in a number of human cancers. Here researchers used a two-stage chemical skin cancer mouse model to investigate whether Stat3 is involved in one of the most common forms of cancer, and if so, at what stage. They found that while a normal mouse, after chemical treatment, developed skin tumors, mice that were deficient in Stat3 were completely resistant to skin tumor development. The authors further showed, both in cell culture and in live animals, that they could block growth of already transformed skin cells if they inhibited Stat3 function using an oligonucleotide inhibitor. Additionally, when skin tumors were injected with this Stat3 functional inhibitor, tumor growth itself was impaired. This study provides the first evidence that Stat3 is required for the initiation of one form of skin cancer, and that it both mediates and maintains cellular growth through expansion of these initiated cells. These data also indicate that Stat3, which has recently begun to emerge as a target for cancer therapy, may also be important for developing cancer prevention strategies.
An accompanying commentary by Jacqueline Bromberg and colleagues, of Memorial Sloan Kettering Cancer Center, provides an overview of Stat3 function in the development of cancer. It places the work by DiGiovanni and colleagues into this context and details how this study advances our understanding of and the development of treatments for cancer.
TITLE: Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis
AUTHOR CONTACT:
John DiGiovanni
The University of Texas M.D. Anderson Cancer Center, PO Box 389, Smithville, TX 78957, USA
Phone: 512-237-9414; Fax: 512-237-2522; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21032.pdf
ACCOMPANYING COMMENTARY: Stat3 is required for the development of skin cancer
AUTHOR CONTACT:
Jacqueline Bromberg
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Phone: 212-639-8191; Fax: 212-422-2231; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/22800.pdf
Pig-Human Transplantation Not PERVerted
Organ or tissue transplantation is a potentially life-saving measure for millions of individuals who have suffered organ failure or require tissue grafts for a variety of reasons. Today thousands die while waiting for suitable organs or tissues to become available. One potential means for relieving this shortage has been through xenotransplantation, that is to use organs or tissues from other organisms, such as pigs. A major concern of xenotransplantation is the possibility of transmitting pathogens from these other species into the donor. Particular attention, for the case of transplantation of tissues and organs from pigs, has been paid to a set of pig-derived viruses called PERVs (for Porcine Endogenous RetroViruses) because they possess the ability, though limited, to replicate in human cells. So far, the actually frequency of PERV transmission within a living organism has not been tested in either patients or animal models under circumstances where human cells are exposed over a long term to similar amount of pig tissue. Yong-Guang Yang and colleagues, from Massachusetts General Hospital/Harvard Medical School, provide new data that indicate the dangers of such viral transmission may be extremely low and that pigs may be a safer source of transplantation material than previously thought. To carry out their assessment, the researchers developed a new xenotransplantation model where human cells coexist with large numbers of porcine cells in a transgenic mouse. The study showed that these cells could in fact coexist long-term without PERV infection in the human cells. Although, the authors did find that human cells in these mice did contain PERV sequences, further investigation proved that this was the result of a mouse retrovirus infecting the pig cells and then transmitting the PERV from there to the human cells. This is not a concern in actual xenotransplantation, but intriguingly may account for previous observations of PERV transmission into human cells in other mouse studies, and indicates the importance of developing robust models that do not contain additional replication capable viruses. Given the absence of direct human cell transmission of PERV, these work supports the potential safety of using pigs as source animals for transplantation to humans.
TITLE: Mouse retrovirus mediates porcine endogenous retrovirus transmission into human cells in long-term human-porcine chimeric mice
AUTHOR CONTACT:
Yong-Guang Yang
Massachusetts General Hospital/Harvard Medical School, 13th Street, Boston, MA 02129, USA
Phone: 617-726-6959; Fax: 617-724-9892; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21946.pdf
Immunity in the Balance
The liver is a place of contradiction; on the one hand it has high tolerance for the presence of some foreign tissues as indicated by its being a good prospect for transplantation, but on the other it also responsible for triggering immune responses to a variety of pathogens and is itself subject to autoimmune diseases. To investigate this paradox, Patrick Bertolino and colleagues used genetically altered mice models that specifically express immune-reactive substrates called antigens in either the liver cells or the hepatic lymph nodes to examine the mechanisms that mediate these paradoxical activities. The authors found that when antigen was present in the lymph nodes, and thus immune cells were activated and began to proliferate in the lymph nodes, there was a strong immunological response that ultimately was followed by the development of hepatitis. If, however, the antigens were in the liver cells, and immune cell activation occurred within the liver tissue, the immune response was defective and did not result in the development of hepatitis. These data indicate that immune cell priming within the lymph nodes is required for automimmune disease in the liver. This study further demonstrates that competition between the liver and lymph nodes as the site of primary immune cell activation plays a major role in determining the balance between tolerance and immunity. This may have important implications for transplantation studies and for the development and treatment of immune-mediated liver disease.
TITLE: The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity
AUTHOR CONTACTS:
Patrick Bertolino
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia
Phone: 61-2-9565-6186; Fax: 61-2-9565-6101; E-mail: [email protected]
David G. Bowen
Columbus Children's Research Institute, 700 Childrens Dr., Columbus, OH 43205, USA
Phone: 614-722-2806; Fax: 614-722-3680; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21593.pdf
A JAM-A in DC Traffic
The transmembrane adhesive protein junctional adhesion molecule (JAM-A) is expressed in a large number of cell types and is present specifically in regions involved in cell-to-cell contact. Elisabetta Dejana and colleagues, at INFOM in Milan, Italy, have now found an additional cell type that expresses JAM-A: dendritic cells (DCs), and have shown that JAM-A plays an important role in dendritic cell motility. After identifying the presence of JAM-A in dendritic cells, the researchers developed a mouse model that completely lacked JAM-A in order to examine its biological role in dendritic cells. Motility studies, both in living animals and in cell culture, showed that in the absence of JAM-A, dendritic cells had increased migration. In JAM-A-/- mice, specifically, there was increased movement of dendritic cells into the lymph nodes. Of further interest, JAM-A�/� mice also had showed a greater immunological reaction when their skin was exposed to an allergen as compared to wild-type mice. Further, wild-type mice that had dendritic cells that came from JAM-A�/� mice transferred into them also showed this enhanced contact hypersensitivity, indicating that the lack of JAM-A in the dendritic cells themselves, rather than an external lack, caused their enhanced motility and their increased ability to respond to potential pathogens. These studies provide evidence that JAM-A is involved in a process that inhibits dendritic cells trafficking to the lymph nodes and the activation of specific immune responses.
TITLE: Increased DC trafficking to lymph nodes and contact hypersensitivity in junctional adhesion molecule-A�-deficient mice
AUTHOR CONTACT:
Elisabetta Dejana
IFOM, via Adamello 16, 20139 Milan, Italy
Phone: 39-02-5743031; Fax: 39-02-574303244; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21231.pdf
NF-kB Protects Young Lung
Acute exposure to an excess of oxygen, called hyperoxia, can cause severe lung damage, but interestingly is more harmful to the adult than to the neonatal lung. The molecular mechanisms that underlie this differential response remain primarily unknown. Phyllis Dennery and colleagues, from the Children's Hospital of Philadelphia, examined, under conditions of hyperoxia, the activity of a protein called NF-kB, which known to be involved in cellular responses to stress. Upon exposure to a hyperoxic environment, the binding function of NF-kB increased in neonatal but not in adult primary lung-cell cultures. To examine NF-kB expression in live animals, the authors used a transgenic mouse that carried the luciferase gene under the control of a portion of the NF-kB promoter; thus, if conditions were such that the NF-kB gene was turned on, the marker gene, luciferase, would be expressed. Such expression can be seen clearly as the luciferase gene product glows. Under hyperoxic conditions, the researchers found, that luciferase expression was higher in the neonatal lung than in that of the adult. Examination of different molecular factors in the NF-kB pathway indicated that NF-kB activity, in addition to its gene expression, was also higher in neonatal lungs as compared to adult lungs from mice. Data also indicated that the mechanism by which NF-kB provided protection was that it blocked damaged cells in the young lung tissue from undergoing programmed cell death. The authors used inhibitory antibodies to further show that the protein p50, a part of the NF-kB complex, is necessary for protection from hyperoxic damage. They then created a mouse that lacked the p50 protein, and found that the p50-/- neonatal mice showed increased lung damage and increased mortality under hyperoxic conditions compared to wild-type mice. These data provide evidence that NF-kB mechanisms of activation change with maturity and may play an important role in protecting the neonatal lung from hyperoxic damage.
TITLE: Maturational differences in lung NF-kB activation and their role in tolerance to hyperoxia
AUTHOR CONTACT:
Phyllis A. Dennery
University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
Phone: 215-590-1653; Fax: 267-426-5632; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/19300.pdf
OTHER PAPERS IN THIS ISSUE
Combination Creates Lupus Nephritis Crisis
TITLE: Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes
AUTHOR CONTACT:
Mohamed R. Daha
Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Phone: 31715263964; Fax: 31715248118; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21075.pdf
ACCOMPANYING COMMENTARY: Anti-C1q autoantibodies amplify pathogenic complement activation in systemic lupus erythematosus
AUTHOR CONTACT:
V. Michael Holers
University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262, USA
Phone: 303-315-7592; Fax: 303-315-5540; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/22820.pdf
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Diabetic-Accelerated Atherosclerosis Distinctions
TITLE: Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions
AUTHOR CONTACT:
Karin E. Bornfeldt
University of Washington School of Medicine, Seattle, Washington 98195, USA
Phone: 206-543-1681; Fax: 206-543-3644; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/17867.pdf
ACCOMPANYING COMMENTARY: Why does diabetes increase atherosclerosis? I don't know!
AUTHOR CONTACT:
Ira J. Goldberg
Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
Phone: 212-305-5961; Fax: 212-305-5484; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/22826.pdf
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ATP as Food for Kidney Feedback
TITLE: Impairment of tubuloglomerular feedback regulation of GFR in ecto-5'-nucleotidase/CD73�deficient mice
AUTHOR CONTACT:
Jurgen Schnermann
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, USA
Phone: 301-435-6580; Fax: 301-435-6587; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21851.pdf
ACCOMPANYING COMMENTARY: Adenosine and ATP: traffic regulators in the kidney
AUTHOR CONTACT:
Wilhelm Kriz
University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany
Phone: 49-6221-54-8680; Fax: 49-6221-54-4951; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/22669.pdf
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Lymphocyte Promotes Parasite Penetration
TITLE: Cerebral vessel laminins and IFN-gamma define Trypanosoma brucei brucei penetration of the blood-brain barrier
AUTHOR CONTACT:
Krister Kristensson
Karolinska Institutet, Retzius v�g 8, SE-171 77 Stockholm, Sweden
Phone: 46-8-728-78-25; Fax: 46-8-32-53-25; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/22104.pdf
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EVI1 Evil in Blood Disease
TITLE: EVI1 induces myelodysplastic syndrome in mice
AUTHOR CONTACT:
Giuseppina Nucifora
University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, IL 60607, USA
Phone: 312-413-2875; Fax: 312-413-0548; E-mail: [email protected].
View the PDF of this article at: https://www.the-jci.org/press/21716.pdf
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Insulin Sympathizers in Sympathetic Nervous System
TITLE: Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin
AUTHOR CONTACT:
William G. Haynes
University of Iowa College of Medicine, Iowa City, IA 52242, USA
Phone: 319-356-8469; Fax: 319-353-7340; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21737.pdf
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Podocyte Proliferation -- Nef Said
TITLE: Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways
AUTHOR CONTACT:
John Cijiang He
Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029, USA
Phone: 212-241-8004; Fax: 212-987-0389; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/21004.pdf
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