Cigarettes are addictive, and smoking them causes lung cancer. Of the two "active ingredients" listed on the packs, scientists had initially assumed that nicotine was the addictive agent, and tar the carcinogen. Recent evidence, however, suggests that things are not that simple, and that nicotine and its derivatives themselves might also promote cancer development and progression. Phillip Dennis and colleagues at the US National Cancer Institute in Bethesda, have studied the effect of nicotine and the nicotine-derived nitrosamine NKK on normal lung epithelial cells--i.e. those cells that are exposed to inhaled smoke and in which lung cancer starts.
As they report in the January 2nd issue of the Journal of Clinical Investigation, stimulation of lung epithelial cells with amounts of nicotine and NKK equivalent to those seen in smokers, resulted in the activation of a molecular pathway -- the so-called Akt pathway -- that promotes cell growth and survival. They also found that the Akt pathway was active in the lungs of mice treated with NKK and in lung cancer tissue from smokers.
This is significant because programmed cell death, or apoptosis, is one of the body's most effective defense mechanisms against cancer. Cells are constantly checking their "normal status", and are poised to commit suicide at the first sign of irregularities, thus protecting the host from propagation of abnormal cells that can, over time, form tumors. Virtually all cancers have found ways to undermine this defense mechanism, and activation of the Akt survival pathway is one of them.
The article is accompanied by a Commentary from John Minna, Director of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center in Dallas, who discusses the findings in the context of other recent results that also suggest that nicotine and its derivatives, in addition to their addictive properties, can directly promote cancer.
In light of the mounting evidence, as Dennis and colleagues suggest, it might become necessary to re-evaluate the risk-benefit ratio of quitting-aids such as nicotine patches, chewing gum, or nasal sprays.
CONTACT:
Phillip Dennis
National Cancer Institute
Bethesda, MD 20889
USA
Phone 1: 301-496-0901
Fax 1: 301-496-0047
E-mail: pdennis@nih.gov
View the PDF of the research article at: https://www.the-jci.org/press/16147.pdf
ACCOMPANYING COMMENTARY:
Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine
receptor expression in the pathogenesis of lung cancer.
CONTACT:
John D. Minna
Hamon Center for Therapeutic Oncology Research, NB8.206
University of Texas Southwestern Medical Center
6000 Harry Hines Boulevard,
Dallas, TX 75390
USA
Phone: 214-648-4900
Fax: 214-648-4940
E-mail: john.minna@utsouthwestern.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17492.pdf
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TABLE OF CONTENTS
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Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors
Basal and squamous cell carcinomas, collectively referred to as nonmelanoma skin cancers, are two of the most common malignancies diagnosed in humans. Manuel Guzman and colleagues have previously shown that cannabinoids can induce the regression of murine gliomas in vivo through activation of the widely expressed CB cannabinoid receptors. On pages xxx-yyy, these authors now demonstrate that CB1, and a second cannabinoid receptor CB2, are expressed in both normal skin and nonmelanoma skin tumors of mice and humans. Administration of CB agonists significantly inhibited skin tumor growth in mice. Two underlying mechanisms seem to be responsible: cannabinoid-treated tumors showed an increase in the number of apoptotic cells, and a decrease in the expression of pro-angiogenic factors such as VEGF and angiopoietin 2. While this suggests that cannabinoids may be utilized in the treatment of skin tumors, further studies will need to investigate their utility as topical therapeutics.
CONTACT:
Manuel Guzman
Department of Biochemistry and Molecular Biology I, School of Biology, Comp
Madrid, NULL 28040
SPAIN
Phone 1: 34-913-944-668
Fax 1: 34-913-944-672
E-mail: mgp@bbm1.ucm.es
View the PDF of this article at: https://www.the-jci.org/press/16116.pdf
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A novel streptococcal surface protease promotes virulence, resistance to opsonophagocytosis, and cleavage of human fibrinogen
The innate immune response is the first line of defense against bacterial infections in the non-immune host. One effective antibacterial strategy is phagocytosis, and virulent bacterial strains have evolved antiphagocytic strategies. Searching for new virulence factors in group B streptococcus, Craig Rubens and colleagues isolated the cspA gene from a highly virulent strain. As they report (pages 61-70), cspA encodes a novel protease that is necessary for the cleavage of human fibrinogen. The protein is localized on the bacterial surface and promotes bacterial survival through evasion of opsonophagocytosis, perhaps through binding of a fibrin-like molecule to the bacterial surface. Genes homologous to cspA exist in other Gram-positive bacteria, suggesting that the mechanism by which it promotes bacterial survival might be common.
CONTACT:
Craig E. Rubens
Division Of Infectious Diseases CH 32
Childrens Hospital & Medical Center
4800 Sand Point Way NE, PO Box C5371
Seattle, WA 98105
Phone 1: 206-526-2073
Fax 1: 206-527-3890
E-mail: cruben@chmc.org
View the PDF of this article at: https://www.the-jci.org/press/16270.pdf
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Massive hepatic apoptosis associated with TGF-beta-1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice
Acute liver failure results from apoptosis and necrosis, and factors that counteract these processes are potentially useful therapeutic agents. Having previously determined that IGF binding protein-1 (IGFBP-1) is required for liver regeneration, Rebecca Taub and colleagues now show (pages 127-137) that IGFBP-1 functions as a survival factor in a mouse model of acute viral hepatitis. A normally sublethal dose of Fas agonist causes massive hepatocyte apoptosis associated with elevated levels of MMP-9 and TGF-b1 in mice lacking IGFBP-1. Pretreatment with IGFBP-1 suppressed MMP-9 and TGF-b1 expression, reduced the level of apoptosis, and also reduced the associated morbidity and hepatic defects. Similar effects were seen in a model of acute toxic damage, suggesting that IGFBP-1 is a general liver survival factor.
CONTACT:
Rebecca Taub
Bristol Myers Squibb
Route. 141 and Henry Clay Road
Experimental Station 400, Room 2418
Wilmington, DE 19880-0400
USA
Phone 1: 302-467-5511
Fax 1: 302-467-6852
E-mail: rebecca.taub@bms.com
View the PDF of this article at: https://www.the-jci.org/press/16712.pdf
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The AMP-activated protein kinase alpha2 catalytic subunit controls whole body insulin sensitivity
The AMP-activated protein kinase (AMPK) has been proposed as a fuel sensor that mediates the cellular response to nutritional variation. Of several existing AMPK isoforms, AMPKa2 is thought to be physiologically active in skeletal muscle. Benoit Viollet and colleagues have generated mice lacking AMPKa2. As they report (pages 91-98), the mutants are normal with respect to body composition and food intake, but exhibit reduced glucose tolerance. The latter is associated with reduced insulin release and decreased insulin sensitivity of peripheral tissues. However, the metabolic function of mutant isolated skeletal muscle and pancreatic islets is normal, suggesting that the origin of the glucose intolerance is located elsewhere. The authors speculate that AMPKa2 exerts its function as a fuel sensor by modulating the activity of the sympathetic nervous system.
CONTACT:
Benoit Viollet
Institut Cochin
24 rue du faubourg Saint Jacques
PARIS, NULL F-75014
FRANCE
Phone 1: 33-144-412-408
Fax 1: 33-144-412-421
E-mail: viollet@cochin.inserm.fr
View the PDF of this article at: https://www.the-jci.org/press/16567.pdf
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src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation
The tyrosine phosphatase SHP-1 functions as a negative regulator of several signal transduction pathways, including those downstream of the T cell and IL-4 receptors. As both of these pathways are thought to be critical for successful Th2 cell development, Toshinori Nakayama and colleagues examined the role of SHP-1 in general Th1 and Th2 cell development, and in Th2-dependent allergic responses. As reported on pages 107-117, they found that heterozygous motheaten mutants -- which lack one copy of SHP-1 -- exhibited elevated levels of Th2 differentiation and Th2-specific cytokine production upon stimulation when compared with wild-type mice. Motheaten heterozygous mice also showed increased allergic responses in an allergic airway inflammation model, suggesting that SHP-1 may function as a negative regulator in the development of allergic responses such as asthma.
CONTACT:
Toshinori Nakayama
Chiba University
Dept. of Medical Immunology
Graduate School of Medicine
1-8-1 Inohana, Chuo-ku
Chiba, 260-8670
JAPAN
Phone 1: 81-43-226-2200
Fax 1: 81-43-227-1498
E-mail: nakayama@med.m.chiba-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/15719.pdf
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Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis
CONTACT:
Soo-Youl Kim
Cornell University, Weill Medical College
Department of Neuroscience
Burke Medical Research Institute
785 Mamaroneck Avenue
White Plains, NY 10605
USA
Phone 1: 914-597-2500
Fax 1: 914-597-2757
E-mail: sykim@burke.org
View the PDF of this commentary at: https://www.the-jci.org/press/15937.pdf
ACCOMPANYING COMMENTARY:
New weapons against inflammation: dual inhibitors of phospholipase A2 and
transglutaminase
CONTACT:
Lucio Miele
University of Illinois at Chicago
Department of Biopharmaceutical Sciences
Cancer Center, room 335
833 S. Wood St., M/C 865
Chicago, IL 60612
USA
PHONE: 312-413-9646
FAX: 312-413-5638
E-mail: lmiele@uic.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17506.pdf
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A novel form of integrin dysfunction involving beta-1, beta-2 and beta-3 integrins
CONTACT:
Nancy Hogg
Leukocyte Adhesion Lab
Lincoln's Inn Fields
ICRF
London, England WC2A 3PX
GREAT BRITAIN
Phone 1: 44-207-269-3255
Fax 1: 44-207-269 3093
E-mail: n.hogg@icrf.icnet.uk
View the PDF of this article at: https://www.the-jci.org/press/14076.pdf
ACCOMPANYING COMMENTARY: Disabling multiple integrins from the inside out
CONTACT:
University of Minnesota
BSBE Bldg. Rm. 6-266
312 Church St. SE
Minneapolis, MN 55455
USA
PHONE: 612-626-6849
FAX: 612-625-2199
E-mail: shimi002@tc.umn.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17526.pdf
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Distinct Progenitor Populations in Skeletal Muscle are Bone Marrow-Derived and Exhibit Different Cell Fates during Vascular Regeneration
CONTACT:
Karen Hirschi
Baylor College of Medicine
One Baylor Plaza
Rm N1030
Houston, TX 77030
USA
Phone 1: 713-798-7771
Fax 1: 713-798-1230
E-mail: khirschi@bcm.tmc.edu
View the PDF of this article at: https://www.the-jci.org/press/16157.pdf
ACCOMPANYING COMMENTARY: Machinations of the marrow
CONTACT:
Nadia Rosenthal
European Molecular Biology Laboratory
Mouse Biology Programme
via Ramarini 32
00016 Monterotondo
Rome, MA
ITALY
PHONE: 39-06-90091-241
FAX: 39-06-90091-241
E-mail: rosenthal@embl-monterotondo.it
View the PDF of this commentary at: https://www.the-jci.org/press/17546.pdf
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Essential role for proteinase activated receptor-2 in arthritis
CONTACT:
William Ferrell
University of Glasgow
Centre for Rheumatic Diseases
Royal Infirmary
10 Alexandra Parade
Glasgow, UNK G31 2ER
GREAT BRITAIN
Phone 1: 44-141-211-4688
Fax 1: 44-141-211-0414
E-mail: w.ferrell@bio.gla.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/16913.pdf
ACCOMPANYING COMMENTARY: PARticipation in inflammation
CONTACT:
Shaun Coughlin
University of California, San Francisco
Room HSE-1300
513 Parnassus Avenue
San Francisco, CA 94143-0130
USA
PHONE: 415-476-6174
FAX: 415-476-8173
E-mail: coughlin@cvrimail.ucsf.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17564.pdf
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A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I
CONTACT:
Nan Wang
Columbia University
Dept. of Medicine
P&S Rm8-401
630 W. 168th Street
New York, NY 10032
USA
Phone 1: 212-305-5789
Fax 1: 212-305-5052
E-mail: nw30@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/16808.pdf
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Journal
Journal of Clinical Investigation