Diagnostics

News From The Journal Of Clinical Investigation, July 20, 2009

TUMOR IMMUNOLOGY: Killing off human tumor cells The proteins RIG-I and MDA-5 are important intracellular sensors of viruses (specifically they detect viral RNA), triggering an antiviral immune response. Robert Besch and colleagues, at Ludwig Maximilian University, Germany, have now identified a new function downstream of RIG-I and MDA-5 activation: they can trigger a signaling pathway that leads to a cell death process known as apoptosis. The authors hope that this function can be harnessed to generate an efficient anticancer therapeutic. A key result in the study indicated that although synthetic molecules that mimic viral RNA and bind RIG-I and MDA-5 triggered the apoptotic cell death pathway in vitro in both human skin cancer cells (specifically cells of the most aggressive form of skin cancer, melanoma) and noncancerous cells, the noncancerous cells were much less sensitive to apoptotic cell death than the melanoma cells. Further, administration of molecules that bind RIG-I and MDA-5 to immunodeficient mice injected with a human melanoma cell line dramatically reduced spreading of the tumor to the lungs, due to apoptotic tumor cell death. The authors therefore suggest that synthetic molecules that bind RIG-I and MDA-5 might have anticancer therapeutic potential due to their ability to trigger tumor cell death by apoptosis. They further suggest that such molecules would also be likely to stimulate antitumor immune responses, further boosting their anticancer effects. In an accompanying commentary, Laurence Zitvogel and Guido Kroemer discuss in more detail the potential for synthetic molecules that bind RIG-I and MDA-5 to elicit synergistic anticancer effects. TITLE: Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells https://www.the-jci.org/article.php?id=37155 AUTHOR CONTACT: Robert Besch Ludwig Maximilian University, Munich, Germany. ACCOMPANYING COMMENTARY TITLE: Anticancer immunochemotherapy using adjuvants with direct cytotoxic effects https://www.the-jci.org/article.php?id=39991 AUTHOR CONTACT: Guido Kroemer INSERM U848, Institut Gustave Roussy, Villejuif, France. HEMATOLOGY: Mopping up hemoglobin stops it constricting blood vessels Some medical conditions, such as hemolytic anemia, sickle cell disease, and severe malaria, are characterized by the destruction of red blood cells. Many of the severe, often life-threatening, symptoms of these diseases are caused by the large amounts of the molecule hemoglobin (Hb) that are released into the blood upon red blood cell destruction; in particular, the ability of Hb to cause blood vessel constriction. There are currently no treatments to target Hb released into the blood. However, a team of researchers, at University Hospital, Switzerland, and the US FDA, Bethesda, has found that inducing expression of the molecule haptoglobin in dogs and administering haptoglobin to guinea pigs reduced the effects of Hb on blood vessel constriction and thereby reduced the severe symptoms caused by large amounts of Hb in the blood. Interestingly, the team, led by Dominik Schaer and Abdu Alayash, induced haptoglobin expression in the dogs by injecting them with the drug prednisone, a glucocorticoid used in the clinic to decrease inflammation. The authors hope that these observations can be translated into potential therapies for diseases associated with red blood cell destruction. In an accompanying commentary, Gregory Kato, at the NIH, Bethesda, suggests that these data might help explain the observation that in double-blind, randomized, placebo-controlled trials glucocorticoids were found to initially reduce some of the symptoms of sickle cell disease. TITLE: Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs https://www.the-jci.org/article.php?id=39115 AUTHOR CONTACT: Dominik J. Schaer University Hospital, Zurich, Switzerland. Abdu I. Alayash US FDA, Bethesda, Maryland, USA. ACCOMPANYING COMMENTARY TITLE: Haptoglobin halts hemoglobin"s havoc https://www.the-jci.org/article.php?id=40258 AUTHOR CONTACT: Gregory J. Kato National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. ONCOLOGY: MicroRNAs block tumor growth MicroRNAs are short, noncoding RNAs that regulate many cellular and developmental events by extinguishing the expression of a plethora of genes. Many microRNAs are downregulated in tumors. Data generated by Carola Ponzetto and colleagues, at the University of Torino, Italy, in xenotransplant models of rhabdomyosarcoma (RMS), a cancer that arises from skeletal muscle progenitors, indicates that reexpression of muscle-specific microRNAs can block tumor growth. Prasun J. Mishra and Glenn Merlino, at the National Cancer Institute, Bethesda, discuss in more detail the clinical promise and pitfalls of microRNA reexpression therapy in an accompanying commentary. In the study, the muscle-specific mircoRNAs miR-1 and miR-206 were barely detectable in tumor tissue from individuals with either form of RMS. Importantly reexpression of miR-206 in RMS cells promoted them to take on characteristics of mature skeletal muscle cells in vitro. Furthermore, it blocked tumor growth in xenografted mice and this was associated with the tumor cells gaining expression of genes active in mature skeletal muscle cells. Further analysis revealed one potential molecular mechanism underlying the anticancer effects of miR-206: miR-206 reexpression in RMS cells abrogated expression of MET, a known tumor-promoting protein that is overexpressed in RMS. The authors suggest that because microRNAs target many genes they might be more effective anticancer therapeutics than drugs that target a single gene/protein. TITLE: The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation https://www.the-jci.org/article.php?id=38075 AUTHOR CONTACT: Carola Ponzetto University of Torino, Torino, Italy. ACCOMPANYING COMMENTARY TITLE: MicroRNA reexpression as differentiation therapy in cancer https://www.the-jci.org/article.php?id=40107 AUTHOR CONTACT: Glenn Merlino National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. HEMATOLOGY: Monoclonal antibodies trigger lysosome-dependent lymphoma/leukemia cell death The drug rituximab has greatly improved survival in patients with any one of several forms of lymphoma and leukemia involving B cells. Despite this success, a significant proportion of patients ultimately relapse with a lymphoma/leukemia that is resistant to rituximab treatment, indicating the need for new therapeutics. In this context, drugs related to rituximab but with an increased ability to eradicate lymphoma/leukemia cells in mouse models might be clinically useful. Mark Cragg and colleagues, at Southampton University School of Medicine, United Kingdom, have now identified the mechanism by which these rituximab-related therapeutics, which are known as type II monoclonal antibodies (mAbs), elicit their increased efficacy. Rituximab is a monoclonal antibody that targets the protein CD20, which is specifically expressed on the surface of B cells. It has been previously classified as a type I mAb because it does not directly trigger B cell lymphoma cell death; type II mAbs directly trigger cell death. In this study, the authors have determined how the type II mAb tositumomab, which targets CD20, directly triggers human lymphoma cell lines and primary chronic lymphocytic leukemia cells to undergo cell death. Specifically, they found that tositumomab triggered a cytoplasmic cell death pathway that involved cellular compartments known as lysosomes and that initiation of this process was linked to the ability of the type II mAb to induce homotypic CD20 adhesion. Importantly, a second type II mAb, which targets a protein other than CD20 (specifically it targets HLA-DR), also triggered homotypic adhesion and lysosome-dependent cell death. The authors, and Kirsten GrГсnbГ¦k and Marja JäättelГ¤, in an accompanying commentary, therefore suggest that because these antibodies and rituximab eradicate lymphoma/leukemia cells by different mechanisms, type II mAbs might be of benefit to individuals with rituximab-resistant disease. TITLE: Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells https://www.the-jci.org/article.php?id=37884 AUTHOR CONTACT: Mark S. Cragg Southampton University School of Medicine, General Hospital, Southampton, United Kingdom. ACCOMPANYING COMMENTARY TITLE: Engaging the lysosomal compartment to combat B cell malignancies https://www.the-jci.org/article.php?id=40259 AUTHOR CONTACT: Marja JäättelГ¤ Institute for Cancer Biology, Danish Cancer Society, Copenhagen, Denmark. IMMUNOLOGY: The protein EBAG9 keeps cytotoxic immune cells in check CTLs are immune cells that have a central role in killing virus-infected cells and tumor cells. They execute this function by secreting cytotoxic agents from intracellular compartments known as lytic granules. New insight into the tight regulation of this cytotoxic process has now been provided by Armin Rehm, Uta E. HГ¶pken, and colleagues, at the Max-DelbrГшck-Center for Molecular Medicine, Germany, who have identified the protein EBAG9 as a negative regulator of mouse CTL cytotoxicity. In the study, CTLs from mice lacking EBAG9 were found to have increased cytotoxicity in vitro and in vivo. This was associated with increased CTL secretion of granzyme A, a characteristic constituent of lytic granules. Further analysis indicated that EBAG9 has a role in regulating the formation of lytic granules and that in its absence cytotoxic agents are more efficiently sorted into these granules. In an accompanying

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