News From The Journal Of Clinical Investigation March 13, 2008

Main Category: Lupus
Also Included In: Clinical Trials / Drug Trials;  Women's Health / Gynecology;  Cancer / Oncology
Article Date: 14 Mar 2008 - 6:00 PDT

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A new road to the autoantibodies that characterize lupus

Systemic lupus erythematosus (SLE), commonly known as lupus, is a chronic autoimmune disease characterized by the inflammatory destruction of many organs, including the skin, joints, and kidneys. A hallmark of the disease is the production of IgG antibodies that target nucleic acid-associated proteins in the nucleus of the individual's own cells (so called autoantibodies). A new study, by Paul Utz and colleagues at Stanford University, has now characterized a new pathway by which immune cells known as B cells can be stimulated to produce these IgG autoantibodies in a mouse model of SLE. Specifically, signaling downstream of B cell recognition of soluble factors known as type I IFNs was found to be required for the production of IgG autoantibodies. Further, these signaling pathways were also required to upregulate the expression of two sensors of the nucleic acid-associated proteins recognized by these IgG autoantibodies (TLR7 and TLR9), an event that stimulates production of IgG autoantibodies. The authors therefore suggested that their data provide a clear rationale for pursuing the development of specific inhibitors of type I IFNs and TLRs for the treatment of individuals with SLE, therapies that are currently in preclinical and/or early-stage clinical trials.

TITLE: IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

AUTHOR CONTACT:
Paul J. Utz
Stanford University School of Medicine, Stanford, California, USA.

The protein MMP-2 helps ovarian tumors stick tight

Ovarian cancer is the fifth leading cause of death from cancer for women in the US. Ovarian tumors transfer to new sites (metastasize) differently from many other tumors - tumor cells are simply released into the fluid that surrounds all the organs in the abdomen and are then able to generate tumors by attaching to new surfaces that support their growth. The membrane that lines the abdomen (the peritoneum) and a large fat pad between the stomach and the small intestine (the omentum) are the most common metastatic sites for ovarian tumors. Determining the molecules and mechanisms involved in the attachment of ovarian tumor cells to these sites is therefore critical for the development of therapeutics. New data, generated by Ernst Lengyal and colleagues at the University of Chicago, have indicated a key role for the protein MMP-2 in this process, leading to the suggestion that some women with ovarian cancer might benefit from early treatment with an MMP inhibitor.

In the study, expression of MMP-2 was upregulated in human ovarian tumor cells when they attached to stromal cells in culture. Further, inhibition of MMP-2 function reduced the attachment of human ovarian tumor cells in a 3D model of metastatic ovarian tumor cell attachment, and reduced their attachment to full human omentum or peritoneum in vitro and to mouse peritoneum and omentum in vivo. Of potential clinical importance, inhibition of MMP-2 function, prior to the dissemination of ovarian tumor cells through the fluid in the abdomen, in immunocompromised mice markedly decreased tumor growth and metastasis and extended survival.

TITLE: The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin

AUTHOR CONTACT:
Ernst Lengyel
University of Chicago, Chicago, Illinois, USA.

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Source: Karen Honey
Journal of Clinical Investigation

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