JCI online early table of contents: March 8, 2010

One treatment being investigated as an adjuvant for anticancer immunotherapies is the use of molecules that trigger the proteins TLR7 and TLR8. For example, the TLR7 stimulant imiquimod is used for the treatment of skin cancer and metastatic melanoma. However, new research, performed by Isabelle Cremer and colleagues, at INSERM U872, Paris, suggests that such approaches should be developed with caution because stimulation of human lung cancer cells with TLR7 or TLR8 agonists increased tumor cell survival and resistance to chemotherapeutics.

TITLE: Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance

AUTHOR CONTACT:
Isabelle Cremer
INSERM U872, Centre de Recherche des Cordeliers, Paris, France.
Phone: 33.1.44.27.90.83; Fax: 33.1.40510420; E-mail: isabelle.cremer@crc.jussieu.fr.

View this article at: http://www.jci.org/articles/view/36551?key=055913a0375e802e2994

Tumors that grow to a certain size need to form new blood vessels if they are to acquire the oxygen and nutrients that are essential for their continued growth and spread to other sites. Although the molecules and signaling pathways that control this new blood vessel growth are potential targets for the treatment of cancer, they have not been completely defined. Using mouse models of cancer, Jadwiga Jablonska and colleagues, at the Helmholtz Centre for Infection Research, Germany, have now identified the soluble factor IFN-beta as a natural inhibitor of tumor blood vessel growth that limits tumor growth and works by repressing in tumor-infiltrating immune cells known as neutrophils the expression of genes responsible for promoting new blood vessel growth. These results provide a potential explanation as to why IFN therapy is beneficial during the early stages of cancer development.

TITLE: Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model

AUTHOR CONTACT:
Jadwiga Jablonska
Helmholtz Centre for Infection Research, Braunschweig, Germany.
Phone: 4953161815110; Fax: 4953161815002; E-mail: jja@gbf.de.

View this article at: http://www.jci.org/articles/view/37223?key=39e734818cb8f194020f

Gene expression in both healthy and cancerous tissues is controlled by a wide array of regulatory molecules including a group of small RNA molecules known as microRNAs. New research, performed by Ethan Dmitrovsky and colleagues, at Dartmouth Medical School, Hanover, now provides evidence that the microRNA miR-31 promotes lung cancer by repressing the expression of a number of tumor suppressor genes (i.e., genes that generate proteins that suppress the development of cancer).

The initial series of experiments conducted in the study indicated that miR-136, miR-376a, and miR-31 were all overexpressed in mouse and human malignant lung tissue compared with paired normal tissue. Importantly, knockdown of miR-31 expression repressed the in vitro growth of mouse and human lung cancer cell lines and reduced the in vivo tumorigenicity of mouse lung cancer cell lines. Further analysis provided a potential mechanism by which modulation of miR-31 expression levels could affect lung cancer cell growth: miR-31 repressed expression of the tumor-suppressor genes LATS2 and PPP2R2A. As miR-31 and these target genes were inversely expressed in human lung cancers, the authors conclude that their data has clinical relevance and that miR-31 promotes lung cancer by repressing expression of specific tumor suppressors.

TITLE: MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors

AUTHOR CONTACT:
Ethan Dmitrovsky
Dartmouth Medical School, Hanover, New Hampshire, USA.
Phone: 603.650.1707; Fax: 603.650.1129; E-mail: ethan.dmitrovsky@dartmouth.edu.

View this article at: http://www.jci.org/articles/view/39566?key=cc0eef96a828a40a885b

Individuals who have abnormally low levels of immune molecules known as antibodies have an increased susceptibility to infection with certain types of bacteria. By analyzing one such person, Jacques J.M. van Dongen and colleagues, at Erasmus MC, University Medical Center Rotterdam, Netherlands, have identified a new genetic cause of antibody deficiency, mutations in the CD81 gene.

Mutations in the CD19 gene, which generates a protein that functions in a complex with CD21, CD81, and CD225, are known to be a cause of antibody deficiency. The patient studied by van Dongen and colleagues had impaired antibody responses and an absence of CD19 expression on B cells (the immune cells that produce antibodies). Surprisingly, no mutations were detected in the patient's CD19 genes. However, mutations were detected in both copies of the CD81 gene, and this was associated with a complete lack of CD81 expression on immune cells in the blood. Further analysis using B cells from the patient revealed that CD81 is required for CD19 membrane expression, providing mechanistic insight into the antibody deficiency caused by CD81 mutation.

TITLE: CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency

AUTHOR CONTACT:
Jacques J.M. van Dongen
Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
Phone: 31.10.7044094; Fax: 31.10.7044731; E-mail: j.j.m.vandongen@erasmusmc.nl.

View this article at: http://www.jci.org/articles/view/39748?key=7c21286c17815d5bcedc

One function of thyroid hormones is to control energy availability and expenditure. Some individuals have mutations in their thyroid hormone receptor-beta (THRB) gene and are resistant to the effects of thyroid hormones. This causes their levels of circulating thyroid hormones to become elevated, but the effects of this have not been completely determined. However, a team of researchers, led by Kitt Falk Petersen and Krishna Chatterjee, at Yale University School of Medicine, New Haven, and Cambridge University, United Kingdom, has now determined that adults and children with THRB mutations have markedly increased resting energy expenditure. Further analysis identified a process known as mitochondrial uncoupling in skeletal muscle, due to tissue selective retention of thyroid hormone receptor-alpha sensitivity to elevated thyroid hormone levels, as a predominant mechanism contributing to this effect. The authors therefore suggest that further studies of individuals resistant to the effects of thyroid hormones will help clarify the relative contribution of different forms of thyroid hormone receptor in different target tissues.

TITLE: Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

AUTHOR CONTACT:
Kitt Falk Petersen
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.785.5447; Fax: 203.737.2174; E-mail: kitt.petersen@yale.edu.

Krishna Chatterjee
University of Cambridge Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge, United Kingdom.
Phone: 44.1223.336842; Fax: 44.1223.330598; E-mail: kkc1@mole.bio.cam.ac.uk.

View this article at: http://www.jci.org/articles/view/38793?key=2a5e777b48bf09b97199

A team of researchers led by Michael Simons, at Yale University School of Medicine, New Haven, has provided new insight into the molecular regulation of arteriogenesis — increase in the diameter of existing arterial blood vessels.

In the study, analysis of mice and zebrafish in which arteriogenesis was defective indicated that the balance between ERK1/2 and PI3K signaling pathways controlled arteriogenesis. Specifically, augmenting ERK1/2 signaling by repressing the PI3K signaling pathway stimulated arteriogenesis. As stimulating arteriogenesis is a therapeutic goal for the treatment of blood vessel diseases caused by conditions such as atherosclerosis (hardening of the arteries), diabetes, and age, the authors suggest that activating the ERK1/2 signaling pathway might be of benefit clinically.

TITLE: ERK1/2–Akt1 crosstalk regulates arteriogenesis in mice and zebrafish

AUTHOR CONTACT:
Michael Simons
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.785.7000; Fax: 203.785.7144; E-mail: michael.simons@yale.edu.

View this article at: http://www.jci.org/articles/view/39837?key=dcd5120a79d33d483231