JCI table of contents: June 22, 2006

June 22, 2006

EDITOR'S PICK

From vomiting to vaccination: Food poisoning bug used to deliver cancer vaccine

By clever design, researchers have devised a way for the bacterium Salmonella typhimurium - often associated with food poisoning - to safely and effectively deliver a vaccine against cancer.

Certain molecules on the surface of cancer cells are either unique or more abundant than those found on non-cancerous cells. These molecules, or antigens, can stimulate the immune system to mount an immune response against the tumor. It is hoped that when a vaccine containing cancer-specific antigens is administered to cancer patients, these antigens will trigger an immune response that targets cancer cells without harming normal cells. Although many cancer vaccine strategies have resulted in measurable immune responses when tested, tumor remission has been observed in only a minority of patients. The identification of new cancer antigens, delivery formulations and vectors is sorely needed.

Since disease-causing bacteria are well equipped to stimulate the immune system, researchers have started to examine the suitability of bacteria that have been genetically manipulated to strip them of their disease-causing ability as delivery vehicles for cancer vaccines. One such bacterium is Salmonella typhimurium, often the culprit in food poisoning in humans. In a study appearing online on June 22 in advance of print publication in the July issue of the Journal of Clinical Investigation, Sacha Gnjatic and colleagues from the Ludwig Institute for Cancer Research constructed an avirulent strain of Salmonella typhimurium endowed with the capacity to deliver the known tumor cell antigen NY-ESO-1. This approach was able to elicit NY-ESO-1-specific CD8+ and CD4+ T cells from lymphocytes taken from cancer patients. Oral delivery of this vaccine to mice resulted in the regression of established NY-ESO-1-expressing tumors. The results of the study suggest that delivery of a cancer vaccine using the Salmonella typhimurium-based delivery system is a promising novel strategy for cancer vaccine development.

TITLE: In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines

AUTHOR CONTACT:
Sacha Gnjatic
Ludwig Institute for Cancer Research, New York, New York, USA.
Phone : (212) 639-8602; Fax: (212) 717-3100; E-mail: gnjatics@mskcc.org.

AUTHOR CONTACT:
Jorge E. Galan
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone : (203) 737-2404; Fax: (203) 737-2630; E-mail: jorge.galan@yale.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28045




ONCOLOGY

DNA vaccine improves chemotherapeutic drug uptake in colon and breast cancer

After the genetic events that initiate malignancy have occurred, tumor progression critically involves interactions between the malignant cells and the normal cells in the tumor environment. An example of such cells are tumor-associated fibroblasts that make collagen type I, which play a role in the poor uptake by tumors of some chemotherapeutic drugs.

In a study appearing online on June 22 in advance of print publication in the July issue of the Journal of Clinical Investigation, Ralph Reisfeld and colleagues from The Scripps Research Institute, California, show that by specifically targeting and killing tumor-associated fibroblasts with an orally delivered DNA-based vaccine, they can significantly suppress the growth and spread of multidrug-resistant colon and breast carcinomas in mice. By disrupting collagen type I expression the authors were able to significantly increase tumor uptake of chemotherapeutic drugs, resulting in tumor rejection and a 3-fold prolongation of lifespan of these mice. This novel technique opens up new and exciting avenues for the improvement of cancer chemotherapy.

TITLE: Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake

AUTHOR CONTACT:
Ralph Reisfeld
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-8105; Fax: (858) 784-2708; E-mail: reisfeld@scripps.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=26532




METABOLIC DISEASE

"To eat or not to eat?": How neuronal potassium channel activity helps us determine the answer

To eat or not to eat: what inputs to the brain help us make this decision? In a study appearing online on June 22 in advance of print publication in the July issue of the Journal of Clinical Investigation, Jens Brüning and colleagues from the University of Cologne investigate the complex answer to this question.

Two types of neurons in the hypothalamus appear to be the chiefs of appetite regulation - the so-called NYP neurons trigger the feeling of hunger and the POMC neurons inhibit it. The activity of each depends on what chemicals these neurons interact with. The hormones leptin and insulin are two such fuel-sensing chemicals and the intracellular pathways via which they signal intersect at an enzyme known as PI3K, which produces the messenger protein PIP3.

Brüning and colleagues examined the role of PIP3-mediated signals in hypothalamic POMC neurons by inactivating the gene for the PIP3 phosphatase Pten in these cells in mice. This resulted in an excessive ingestion of food beyond what was needed by these animals and diet-induced obesity. Leptin administration failed to significantly inhibit food intake. Interestingly, POMC neurons showed a reduced firing rate that was determined to be due to increased activity of ATP-sensitive potassium channels (KATP channels). The results of this study indicate that KATP channel activity in POMC neurons plays a critical role in regulating POMC activity and consequently the inhibition of the sensation of hunger. Further exploration of this signaling pathway may help to define novel approaches to the treatment of obesity and diabetes.

TITLE: Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

AUTHOR CONTACT:
Jens C. Brüning
University of Cologne, Cologne, Germany.
Phone: 49-221-470-2467; Fax: 49-221-470-5185; E-mail: jens.bruening@uni-koeln.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27123




VIROLOGY

New mouse model of Kaposi sarcoma-associated herpesvirus infection

Recent studies have implicated human herpesviruses as the causative agents of a number of illnesses in HIV-1-positive individuals or patients receiving medication that suppresses their immune system. Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is the cause of Kaposi sarcoma, the most common AIDS-associated malignancy. While highly active antiretroviral therapy for HIV-1 infection has reduced the incidence of Kaposi sarcoma, progression or regression of tumors is often incomplete. Most studies of KSHV infection have been limited to cell culture systems. As such, a better understanding of KSHV infection has hinged on the development of an animal model of disease suitable for study and in which potential anti-KSHV therapeutics could also be tested.

In a study appearing online on June 22 in advance of print publication in the July issue of the Journal of Clinical Investigation, Dean Kedes and colleagues at the University of Virginia describe the creation of an in vivo mouse model of KSHV infection. The authors intravenously injected non-obese diabetic/severe combined autoimmune-deficient (NOD/SCID) mice with purified KSHV and were able to show long-term latent and lytic infection with KSHV. They went on to show that the virus establishes infection in B cells, macrophages, natural killer cells, and dendritic cells in these animals. Importantly, viral growth was dramatically inhibited by administration of the antiviral drug ganciclovir.

This mouse model promises to be a powerful tool to study the pathogenesis of KSHV, including the role of viral genes in infection and disease formation, as well as the host response to these processes.

TITLE: KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice

AUTHOR CONTACT:
Dean H. Kedes
University of Virginia, Charlottesville, Virginia, USA.
Phone: (434) 243-2758; Fax: (434) 982-1071; E-mail: kedes@virginia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27249
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