August 10, 2010

News From Journal Of Clinical Investigation Online: Aug. 9, 2010

Article Date: 10 Aug 2010 - 4:00 PDT

ONCOLOGY: Identifying liver cancer stem cells

A subpopulation of cells in a tumor that are known as cancer stem cells (CSCs) are thought to be involved in tumor resistance to chemo/radiation therapy as well as tumor relapse and progression. However, whether CSCs exist in many cancers and what their identity is has been hard to determine. A team of researchers, led by Masaki Mori, at Osaka University, Japan, has now determined that CD13 is a marker for CSCs in human liver cancer cell lines and clinical samples. Furthermore, combining a CD13 inhibitor with the chemotherapeutic agent 5-FU drastically reduced tumor volume compared with either agent alone in mouse xenograft models, leading the authors to suggest that targeting the CD13+ CSCs might provide a way to treat patients with liver cancer.

CD13 is a therapeutic target in human liver cancer stem cells

DRUG DEVELOPMENT: Improving RNAi efficacy, toxicity, and persistence

In several clinical trials, RNAi-based therapies have been shown to be effective and well tolerated. However, animal studies suggest that there is a need for caution, as RNAi can trigger cell death leading to organ failure and lethality. It is believed that these adverse effects are a result of saturation of endogenous cellular RNAi factors such as Xpo-5. A team of researchers, led by Mark Kay, at Stanford University, California, has now generated substantive data in mice to support the idea that RNAi-based therapies overload the endogenous RNAi pathway to cause liver damage, and developed ways to overcome this problem.

In the study, members of the human Ago family of proteins were found to be involved in saturation of endogenous cellular RNAi, with Ago-2 particularly prone to saturation and acting as a rate-limiting determinant of both in vitro and in vivo RNAi efficacy, toxicity, and persistence. The authors then developed two ways to enhance RNAi efficacy and persistence while decreasing toxicity, approaches that they hope will improve human RNAi-based therapies. First, in adult mice, vector-based Ago-2/Xpo-5 coexpression enhanced RNAi silencing in the liver, reduced liver damage, and extended RNAi stability. Second, minimizing shRNA expression reduced liver damage while still permitting long-term gene silencing.

Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver

ONCOLOGY: Subdividing cancers in mice identifies distinct human tumor subtypes

Some cancers can be divided into subtypes depending on the signaling pathways that drive tumor development. This can help determine which therapy is most appropriate, for example breast cancers lacking expression of the proteins to which hormones bind do not respond to hormone-based therapies. A team of researchers, led by Rama Khokha, at Ontario Cancer Institute, Toronto, has now generated a new mouse model of osteosarcoma (the most common type of bone tumor) and found that deletions of the Prkar1a gene characterize a molecularly distinct subtype of mouse osteosarcoma featuring overexpression of the protein RANKL. Human tumors could also be divided based on high and low expression of PRKAR1A, with low levels of expression being associated with a greater likelihood of responding to chemotherapy. The authors therefore conclude that information gleaned in mice can help divide human tumors into clinically relevant subtypes.

Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice

CARDIOVASCULAR DISEASE: Heart protection via myeloid MR

Drugs that target the protein MR are used to treat diseases of the blood vessels and heart (i.e., cardiovascular diseases). Although some of their benefit is a result of blocking binding of the steroid hormone aldosterone to MR, data indicate that some of their effects are aldosterone independent. A team of researchers, led by Richard Mortensen, at the University of Michigan Medical School, Ann Arbor, and Sheng Zhong Duan, at Shanghai Institutes for Biological Sciences, China, has now shown that mice lacking MR on immune cells known as myeloid cells are protected against heart and blood vessel damage in the same way that mice treated with drugs targeting MR are. Further analysis indicated that MR on myeloid cells is necessary for efficient classical activation of myeloid immune cells known as macrophages by proinflammatory cytokines. These data provide new insight into the mechanisms underlying the beneficial effects of drugs that target MR.

Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice

Karen Honey
Journal of Clinical Investigation


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