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JCI online early table of contents: Feb. 8, 2010

EDITOR'S PICK: Marker of Ewing sarcoma: potential new drug target?

Ewing sarcoma (EWS) is a bone tumor of unknown cellular origin that affects children and young adults. The protein CD99 is highly expressed in most cases of EWS, but its function in the disease is unknown. Now, Katia Scotlandi and colleagues, at SSN Emilia Romagna Istituto Ortopedico Rizzoli IRCCS, Bologna, Italy, have identified a crucial role for CD99 in the development of EWS and suggest that targeting CD99 or its downstream molecular pathway may be a new therapeutic approach for EWS.

In the study, decreasing CD99 expression in human EWS cell lines reduced their ability to form tumors xenografted into mice. In vitro, it increased expression of H-neurofilament, a marker of neuronal differentiation. Consistent with this, an inverse correlation between CD99 expression and H-neurofilament expression, neural differentiation, and oncogenic transformation was observed in patient-derived EWS cells. The authors therefore conclude that CD99 prevents neural differentiation and suggest that blocking it might provide a new approach to treating EWS.

TITLE: CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis

Katia Scotlandi
SSN Emilia Romagna Istituto Ortopedico Rizzoli IRCCS, Bologna, Italy.
Phone: 39.051.6366760; Fax: 39.051.6366763; E-mail:

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EDITOR'S PICK: Enhancing arrest of cell growth to treat cancer in mice

A team of researchers, led by Pier Paolo Pandolfi, at Beth Israel Deaconess Medical Center, Boston, has identified a new type of cellular senescence (i.e., irreversible arrest of cell growth) and determined a way to enhance it to suppress prostate tumor development and growth in mice.

Previous work by Pandolfi and colleagues determined that inactivation of the protein Pten leads to a senescence response that opposes tumorigenesis. In this study, Pten-lossinduced cellular senescence (PICS) was found to be distinct from another form of cellular senescence known as oncogene-induced senescence in that it did not cause cellular proliferation and DNA damage. This was important because these two consequences of oncogene-induced senescence mean that enhancing this process for the treatment of cancer is not a viable option. As pharmacological inhibition of PTEN was found to drive senescence and inhibit tumor development and growth in vivo in a human xenograft model of prostate cancer, the authors suggest that enhancing PICS might provide a new approach for cancer prevention and therapy.

TITLE: A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis

Pier Paolo Pandolfi
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Phone: 617.735.2121; Fax: 617.735.2120; E-mail:

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NEPHROLOGY: New approach to treating the kidney disease Alport syndrome?

Alport syndrome is a progressive hereditary kidney disease with no definitive therapy. It is caused by mutations in any of the collagen IV genes (COL4A3, COL4A4, and COL4A5). Motoko Yanagita and colleagues, at Kyoto University Graduate School of Medicine, Japan, have now identified a role for the protein USAG-1 in the development of disease in mice that model Alport syndrome (Col4a3/ mice). As deletion of Usag1 in Col4a3/ mice led to substantial attenuation of disease progression, preservation of kidney function, and extension of life span, the authors suggest that inhibiting USAG-1 might be a promising therapeutic approach for the treatment of Alport syndrome.

TITLE: Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

Motoko Yanagita
Kyoto University Graduate School of Medicine, Kyoto, Japan.
Phone: 81.75.753.9310; Fax: 81.75.753.9311; E-mail:

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HEMATOLOGY: Role for the protein HIF-2-alpha in Chuvash polycythemia

Individuals with a condition known as Chuvash polycythemia, which is caused by a specific mutation in the protein VHL, have a greater proportion of their blood volume occupied by red blood cells than do healthy individuals. They also have pulmonary hypertension (i.e., increased blood pressure in the blood vessels that go to and from the lung) and increased respiratory rates, although the mechanistic basis for these symptoms has not been determined. Now, Celeste Simon and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have identified a role for the protein HIF-2-alpha in the lung complications of Chuvash polycythemia by studying mice that model the condition. Of particular interest, HIF-2-alpha activity was found to be increased in lungs from mice that model Chuvash polycythemia. Further, as loss of one copy of the gene responsible for generating HIF-2-alpha in mice that model Chuvash polycythemia suppressed both the polycythemia and pulmonary hypertension, the authors suggest that inhibiting HIF-2-alpha might provide a new approach to treat Chuvash disease.

TITLE: The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice

M. Celeste Simon
University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Phone: 215.746.5532; Fax: 215.746.5511; E-mail:

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ONCOLOGY: Rab25: a suppressor of tumor formation in intestines?

Colorectal adenocarcinoma accounts for the majority of cases of colorectal cancer. A series of genetic mutations in the cells lining the colon (intestinal epithelial cells) is thought to be the cause of colorectal adenocarcinoma. By studying mouse models of colon cancer and tissue from individuals with colorectal adenocarcinoma, James Goldenring and colleagues, at Vanderbilt University School of Medicine, Nashville, have now identified RAB25 as one gene that might be involved in the formation of colorectal adenocarcinomas.

Initial analysis indicated that expression of Rab25 was substantially decreased in human colon adenocarcinomas compared with normal colon and that lower Rab25 expression predicted shorter patient survival times. To follow up on these data, which suggested that Rab25 functions as a tumor suppressor (that is, a protein that when expressed at lower than normal levels due to mutation of the gene responsible for its generation fails to prevent tumors forming) in intestinal epithelial cells, the authors analyzed Rab25-deficient mice. Although these animals showed no gross abnormalities, when they were crossed with mice that model a hereditary syndrome that predisposes to colon cancer (ApcMin/+ mice), the Rab25-deficient ApcMin/+ mice developed increased numbers of intestinal polyps and colonic tumors compared with parental ApcMin/+ mice. Similar results were obtained in a second mouse model of colorectal adenocarcinoma, providing further confirmation of the probable tumor suppressor role of Rab25 in intestinal epithelial cells.

TITLE: Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas

James R. Goldenring
Vanderbilt University School of Medicine, Nashville, TN, USA.
Phone: 615.936.3726; Fax: 615.343.1591; Email:

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IMMUNOLOGY: Complete chemokine profile of a cell

Chemokines are a large group of proteins whose predominant function is to direct cell migration. They regulate many physiological and pathophysiological processes, in particular in the immune system. Dirk Homann and colleagues, at University of Colorado Denver, Aurora, have now developed a simple method to efficiently identify all the chemokines produced by a single cell type, something that has not been possible before.

The method developed by Homann and colleagues is a flow cytometrybased assay that uses commercially available chemokine-specific antibodies to efficiently detect within cells 37 of 39 mouse chemokines. Using this technique, the author were able to delineate the complete chemokine profiles of two types of immune cell (NK cells and B cells) in response to major polyclonal stimuli and to assess the chemokine response of immune cells known as DCs to bacterial infection. Importantly, the authors were able to adapt the method to analyze chemokine expression in human cells, leading them to suggest that this method will help researchers understand the roles of chemokines in health and disease.

TITLE: Comprehensive assessment of chemokine expression profiles by flow cytometry

Dirk Homann
University of Colorado Denver, Aurora, CO, USA.
Phone: 303.724.6843; Fax: 303.724.6830; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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