Many potentially effective cancer treatments are undone by the onset of resistance to the treatment. In order to circumvent this problem, D. Gary Gilliland and colleagues, of Brigham and Women's Hospital, have developed a strategy using the latest technologies involving small interfering RNA to enhance cancer treatment even in a situation where drug resistance has developed. Small interfering RNAs work by inhibiting the expression of specific genes that have a matching complimentary sequence. The authors theorized that this type of RNA treatment might boost the effectiveness of anti-cancer treatments. They tested their theory in a form of leukemia that is caused when two genes fuse to form an unregulated gene that transforms normal cells into cancer cells, a gene called TEL-PDGFbetaR. This form of leukemia is generally treated with a commonly used anti-cancer drug called imatinib, which is a small molecule protein inhibitor that blocks the activity of the protein produced from the fusion gene TEL-PDGFbetaR. Gilliland and colleagues created a small inhibitory RNA specific to the TEL-PDGFbetaR fusion gene, and found that its expression did indeed exclusively reduce the expression of the oncogenic TEL-PDGFbetaR by 90%. While this alone was not sufficient to kill the cancer cells, this treatment enhanced the ability of imatinib to kill these cancer cells. Further, when they tested this strategy with imatinib-resistant cells, the inhibitory RNA was still able to reduce this gene's expression, and enhanced the activity of another small molecule inhibitor. This study demonstrates that small inhibitory RNA treatment may be an extremely useful adjunct to cancer treatments, and can also aid in overcoming the common problem of drug resistance when used in conjunction with anticancer agents.
TITLE: Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin
AUTHOR CONTACT:
D. Gary Gilliland Brigham and Women's Hospital, Boston, Masachusetts, USA.
Phone: (617) 355-9092; Fax: (617) 355-9093; E-mail: ggilliland@rics.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/20673.pdf
Imaging the healing heart
The ability to visualize the healing of damaged tissue after a heart attack is vital for obtaining appropriate therapies for heart patients. Albert Sinusas and colleagues, from Yale University School of Medicine, have now developed a noninvasive method for imaging this process. Following a heart attack, new blood vessels are formed during the healing and remodeling process. In order to encourage healing, therapies for post-heart attack recovery have focused on enhancing factors that induce new blood vessel growth, but evaluation of the efficacy of these strategies is difficult due to the lack of accurate means to measure the thera-peutic effect. Now, Sinusas and colleagues, by radioactively labeling a protein that is present specifically in newly developing blood vessels (a protein called avB3 integrin), have found they could actually track the process of blood vessel growth in the hearts of rat and canine heart-attack models using standard tomography methods. By taking multiple, timed images of the heart, the authors could detect changes in the presence of the marker-protein in the areas damaged during the heart attack. They found that this marker specifically increased in these damaged areas as new blood vessels developed, and allowed clear view of changes in the damaged area over time. Since this method is both non-invasive and uses standard imaging technology, it is an ideal new tool for monitoring changes of damaged areas in patients after a heart attack and during therapeutic trials of potential drugs to enhance such healing.
TITLE: Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction
AUTHOR CONTACT:
Albert J. Sinusas Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-4915; Fax: (203) 737-1026; E-mail: albert.sinusas@yale.edu
View the PDF of this article at: https://www.the-jci.org/press/20352.pdf
Turning Bone into Nerve
The sources used for stem cell treatment of neurodegenerative diseases are currently limited to embryonic stem cells or to adult stem cells of neuronal lineage. It is essential to find additional cellular sources to treat these debilitating diseases given the limited number of embryonic stem cell lines available. Mari Dezawa and colleagues, from Kyoto University, now show that adult stem cells from bone marrow can also be changed into neuronal cells and that these cells benefited a Parkinson disease rat model. The authors induced the bone marrow cells to become neuronal cells by transferring a portion of a gene called Notch that influences the development of neuron cells. After the bone marrow cells were given a portion of the Notch gene, they were treated with growth factors and were found to display typical neuronal characteristics and activities. The therapeutic potential of these cells was confirmed by their transplantation into a rat model of Parkinson disease where there was subsequent restoration of neuronal function.
TITLE: Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation
AUTHOR CONTACT:
Mari Dezawa Kyoto University Graduate School of Medicine, Kyoto, Japan.
Phone: +81-75-753-4343; Fax: +81-75-751-7286; E-mail: dezawa@anat2.med.kyoto-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/20935.pdf
Maximizing Minigene Anticancer Vaccines
Anticancer vaccines provide an attractive approach for the elimination of tumors and the prevention of relapse. The lack of appropriate model systems, however, has made it particularly difficult to test the efficacy and safety of such vaccines. Ralph Reisfeld and colleagues have now constructed a special mouse model that allowed them to effectively create and test a minigene DNA vaccine. The DNA in these anti-cancer vaccines code for a tumor antigen, a protein found on the surface of tumor cells. Upon entry into an organism, the vaccine elicits a response from cells in the immune system, making them target and kill cells that have this antigen on their surface. Some DNA vaccines present the entire antigen gene. Minigene vaccines however, contain only a portion of the antigen gene and can provide greater specificity in the immune response. The tumor antigen called carcinoembryonic antigen is an especially interesting target for a DNA vaccine because carcinoembryonic antigen is overexpressed in most colorectal, gastric, and pancreatic cancers, and in about 50% of breast cancers, and 70% of non–small cell lung cancers. In order to develop such a vaccine, Reisfeld and colleagues had to construct a special mouse that expresses both the human carcinoembryonic antigen, so the mice would not have an immune response against the vaccine itself, and also human major histocompatibility genes, so that the mouse was able to carry out antigen presentation to the immune cells in a manner similar to that done in humans. Using this mouse system, the authors developed and tested a new and effective carcinoembryonic-antigen minigene vaccine that blocked the growth human colon cancer cells implanted in mice. The work here provides both an efficacious model for testing DNA vaccines, and also provides an alternative design for carcinoembryonic-antigen–based DNA vaccines with potential clinical use.
TITLE: A novel transgenic mouse model for immunological evaluation of carcinoembryonic antigen-based DNA minigene vaccines
AUTHOR CONTACT:
Ralph A. Reisfeld The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-8110; Fax: (858) 784-2708; E-mail: reisfeld@scripps.edu
View the PDF of this article at: https://www.the-jci.org/press/21107.pdf
Collaborations in Cancer
Human plasma cell neoplasms develop when certain blood cells, called plasma cells, become cancerous. Multiple mylomas are the most common form of this type of cancer. Plasma cell neoplasms are difficult to study they often develop through the interaction of more than one mutated gene, and currently there are no good models available. Siegfried Janz and colleagues, from the National Cancer Institute at the NIH have now created such a model system and examined the effect of having two altered genes. Here, they dissect the roles of two genes, c-Myc and Bcl-XL, that are commonly found to be altered in plasma cell neoplasms. They created and characterized three different types of mice: one that over-expressed c-Myc; one that carried a mutated form of Bcl-XL; and one that carried altered forms of both genes. Although some of the characteristics seen in plasma cell neoplasm patients were present in the mice that carry one altered gene, the mice that carried altered forms of both genes all developed severe plasma cell tumors. The authors provide detailed characterization of the differences in these mice and the manner in which the two genes interact to rapidly accelerate cancer development. These mice provide a new model for plasma cell neoplasm formation and will be an essential tool for the development of new anti-tumor strategies.
TITLE: Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice
AUTHOR CONTACT:
Siegfriend Janz National Cancer Institute, Bethesda, Maryland, USA.
Phone: (301) 496-2202; Fax: (301) 402-1031; E-mail: sj4s@nih.gov
View the PDF of this article at: https://www.the-jci.org/press/20369.pdf
Liver Disease Scores a PTEN
An unexpected link has been found between liver cancer and a liver disease called nonalcoholic steatohepatitis. The link is the absence of a known tumor suppressor gene called PTEN. PTEN normally regulates numerous cellular activities including cellular proliferation and mechanisms to block cell death. It is already known that about one half of all liver cancers show a decrease or loss of expression of the PTEN gene. Surprisingly, however, Akira Suzuki and collaborators, from Akita University, now report a new role for this tumor suppressor gene. The researchers found that a lack of PTEN in the liver leads to irregulation of metabolism in liver cells. In order to identify this new role, the authors created mice that had no PTEN gene specifically in the cells of their livers. These mice showed all the characteristic pathologies of a human disease called nonalcoholic steatohepatitis, a disease similar to alcohol-induced liver disease, but found in individuals who do not abuse alcohol. Of interest, the researchers were also able to trace the effects here to the increased expression of a gene that is involved in fat cell differentiation, PPAR_amma. In addition to having the hallmarks of nonalcoholic steatohepatitis, by 40 weeks of age, most of these mutant mice developed liver tumors as well. These results link the development of liver cancer and steatohepatitis and suggest new therapeutic strategies for combating both diseases.
TITLE: Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
AUTHOR CONTACT:
Akira Suzuki Akita University School of Medicine, Akita, Japan.
Phone: +81-18-884-6077; Fax: +81-18-884-6077; E-mail: suzuki@med.akita-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/20513.pdf
Other Papers in this Issue
Coordinated Interactions in Cleft Palate
TITLE: Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate
AUTHOR CONTACT:
David Rice King's College, London, United Kingdom
Phone: +44-207-955-5000 ext.6216; Fax: +44-207-955-2704; E-mail: david.rice@kcl.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/20384.pdf
ACCOMPANYING COMMENTARY: Cleft palate: players, pathways, and pursuits
AUTHOR CONTACT:
Jeffrey C. Murray University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-6897; Fax: (319) 335-6970; E-mail: jeff-murray@uiowa.edu
View the PDF of this commentary at: https://www.the-jci.org/press/22154.pdf
Female Skin Made to Tolerate Male Skin
TITLE: Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby
AUTHOR CONTACT:
Paul J. Fairchild University of Oxford, Oxford, United Kingdom.
Phone: +44-1865-275606; Fax: +44-1865-275501; E-mail: Paul.Fairchild@path.ox.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/20569.pdf
ACCOMPANYING COMMENTARY: Is transplantation tolerable?
AUTHOR CONTACT:
Terry B. Strom Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/22153.pdf
Enter the Ribosome: Poliovirus Attenuates
TITLE: Poliovirus tropism and attenuation are determined after internal ribosome entry
AUTHOR CONTACT:
Vincent R. Racaniello Columbia University College of Physicians and Surgeons, New York, NY, USA.
Phone: (212) 305-5707; Fax: (212) 305-5106; E-mail: vrr1@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/21323.pdf
ACCOMPANYING COMMENTARY: Poliovirus proves IRES-istible in vivo
AUTHOR CONTACT:
Bert L. Semler University of California, Irvine, California, USA.
Phone: (949) 824-7573; Fax: (949) 824-2694; E-mail: blsemler@uci.edu
View the PDF of this commentary at: https://www.the-jci.org/press/22139.pdf
Set Lasers on Stun to Define Lupus Nephritis
TITLE: Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli
AUTHOR CONTACT:
Karin S. Peterson Columbia University, Department of Pediatrics, New York, New York, USA.
Phone: 212-305-5766; Fax: 212-305-9078; E-mail: ksp4@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/19139.pdf
Death by Nitric Oxide
TITLE: Inducible nitric oxide synthase in T cells regulates T cell death and immune memory
AUTHOR CONTACTS:
Vineeta Bal National Institute of Immunology, New Delhi, India.
Phone: +91-11-2-670-3695; Fax: +91-11-2-616-2125; E-mail: vineeta@nii.res.in
Jeannine M. Durdik University of Arkansas, Fayetteville, Arkansas 72701, USA.
Phone: 479-575-8375; Fax: 479-575-4010; E-mail: jdurdik@uark.edu
View the PDF of this article at: https://www.the-jci.org/press/20225.pdf
Brain Injury Repair Requires DNA Repair
TITLE: Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase
AUTHOR CONTACT:
Matthais Endres Charite-Universitatsmedizin Berlin, Berlin, Germany.
Phone: +49-30-450-560-020; Fax: +49-30-450-560-932; E-mail: matthias.endres@charite.de
View the PDF of this article at: https://www.the-jci.org/press/20926.pdf
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