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JCI online early table of contents: Feb. 1, 2012
Date:2/1/2012

EDITOR'S PICK: A thought-provoking new therapeutic target for brain cancer?

Glioblastoma multiforme (GBM) is the most common of all malignant brain tumors that originate in the brain. Patients with GBM have a poor prognosis because it is a highly aggressive form of cancer that is commonly resistant to current therapies. New therapeutic approaches are therefore much needed. Joanna Phillips, Zena Werb, and colleagues, at the University of California, San Francisco, have now identified a potential new therapeutic target for the treatment of GBM.

A substantial proportion of GBMs show evidence of abnormal activation of signaling pathways triggered by a cell surface protein known as PDGFR-alpha, and this is thought to drive the tumor. PDGFR-alpha triggers activation of signaling pathways when it binds the growth factor PDGF. Phillips, Werb, and colleagues found that the protein SULF2, which is known to regulate the availability of growth factors such as PDGF, was expressed in primary human GBM tumors and cell lines. Moreover, GBMs characterized by abnormal activation of signaling pathways downstream of PDGFR-alpha showed the strongest SULF2 expression. Importantly, knocking down expression of SULF2 in human GBM cell lines decreased the growth of these cells upon transplantation into mice. Phillips, Werb, and colleagues therefore suggest that SULF2 is a candidate therapeutic target for the treatment of GBM and that assessing its levels could identify tumors dependent on growth factors such as PDGF. The latter is important as PDGFR-alpha and other molecules to which growth factors bind are themselves good therapeutic targets.

TITLE: Heparan sulfate sulfatase SULF2 regulates PDGFR-alpha signaling and growth in human and mouse malignant glioma

AUTHOR CONTACT:
Joanna J. Phillips
University of California, San Francisco, San Francisco, California, USA.
Phone: 415.514.4929; Fax: 415.514.9792; E-mail: joanna.phillips@ucsf.edu.

Zena Werb,
University of California, San Francisco, San Francisco, California, USA.
Phone: 415.476.4622; Fax: 415.476.4565; E-mail: zena.werb@ucsf.edu.

View this article at: http://www.jci.org/articles/view/58215?key=7d9ee1ebe13cc1c6c025


ONCOLOGY: Answers to age-old questions surrounding fat cell cancer

Myxoid round cell liposarcoma (MRCLS) is a cancerous tumor that typically arises in deep fat tissues of the limbs or abdomen. It was shown almost 20 years ago to be characterized by a chromosomal change that generates a fusion protein known as TLS:CHOP. Despite this, neither the cell from which MRCLS arise nor the mechanism(s) by which TLS:CHOP induces tumor formation have been definitively determined. A team of researchers led by Igor Matushansky, at Columbia University, New York, has now provided some answers to these questions; in doing so, they identified a potential new combination therapy for the treatment of MRCLS.

A compound isolated from the sea squirt Ecteinascidia turbinate, ET-743, is a highly effective therapy for patients with MRCLS, but how it works has not been determined. Using a new mouse model of MRCLS that they developed, Matushansky and colleagues found that expression of TLS:CHOP in endogenous mesenchymal stem cells led to the in vivo development of MRCLS and that ET-743 worked by decreasing expression of TLS:CHOP. Moreover, combining ET-743 treatment with administration of agonists of the protein PPAR-gamma improved survival of the mice. Matushansky and colleagues therefore suggest that ET-743 plus PPAR-gamma agonist could provide a rational combination for treating MRCLS.

TITLE: PPAR-gamma agonists enhance ET-743induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

AUTHOR CONTACT:
Igor Matushansky
Columbia University, New York, New York, USA.
Phone: 212.851.4556; Fax: 212.851.4784; E-mail: im17@columbia.edu.

View this article at: http://www.jci.org/articles/view/60015?key=ace2cdfd6a47aee95dac


TUMOR IMMUNOLOGY: Access denied: dense matrix blocks immune cell path to cancer cells

An individual's immune system does respond to a tumor. However, in individuals diagnosed with cancer, the antitumor response was obviously inadequate to clear the tumor. It is hoped that understanding how tumors escape the antitumor immune response will identify candidate therapeutic approaches, with the rationale being that if the escape mechanism can be blunted then an individual's immune system will be able to destroy the tumor. In this context, a team of researchers led by Emmanuel Donnadieu, at Institut Cochin, France, has determined that in human lung tumors, immune cells known as T cells are rarely found in the clusters of cancer cells. Rather, they accumulate in the stromal region of the tumors (that is, the tissue that surrounds and supports the cancer cells). Moreover, Donnadieu and colleagues found that the T cells could not enter the cancer cell regions because a dense matrix that the T cells could not penetrate surrounded these regions. Treating human lung tumor slices with matrix-degrading compounds increased the ability of T cells to enter the cancer cell clusters. Donnadieu and colleagues hope that future studies will increase understanding of the mechanisms by which the dense matrix is generated and thereby identify potential new therapeutic approaches.

TITLE: Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors

AUTHOR CONTACT:
Emmanuel Donnadieu
INSERM U1016, Institut Cochin, Paris, France.
Phone: 33.1.40.51.65.64; Fax: 33.1.40.51.65.55; E-mail: emmanuel.donnnadieu@inserm.fr.

View this article at: http://www.jci.org/articles/view/45817?key=3f332821bf27bc9a78d3


VIROLOGY: Finally, experimental transformation of a primary cell into a tumor cell by the cancer-causing virus KSHV

Kaposi sarcoma herpesvirus (KSHV) is the causative agent of several cancers that arise most commonly in individuals with HIV/AIDS. Developing therapeutic approaches to treat individuals with these cancers is hampered by a lack of understanding of the mechanisms by which KSHV transforms normal cells into cancerous cells. This is poorly understood in part because researchers have been unable to experimentally infect a primary cell with KSHV and turn it into a cancer cell. However, Shou-Jiang Gao and colleagues, at the University of Texas Health Science Center at San Antonio, San Antonio, have now done just that.

Gao and colleagues found that KSHV efficiently infects primary rat embryonic metanephric mesenchymal precursor cells and transforms them into cells that form tumors when injected into mice. They hope to use this model to study the molecular mechanisms by which KSHV transforms normal cells into cancerous cells, although they caution that additional analysis would be required to determine whether mechanisms uncovered using transformed rat cells are relevant to human cancers caused by KSHV.

TITLE: Direct and efficient cellular transformation of primary rat mesenchymal precursor cells by KSHV

AUTHOR CONTACT:
Shou-Jiang Gao
University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Phone: 323.442.8028; Fax: 323.442.1721; E-mail: shoujiag@usc.edu.

View this article at: http://www.jci.org/articles/view/58530?key=b593e40b17636db485f1


ONCOLOGY: Taking on features of cancer cells

The protein p27Kip1 has a role in suppressing tumor development and progression. It does so by inhibiting the activity of protein complexes that promote cell proliferation (cyclincyclin-dependent kinase complexes). In contrast, mutant forms of p27Kip1 that cannot inhibit cyclincyclin-dependent kinase complexes promote tumor development in mice. Now, a team of researchers led by Arnaud Besson, at INSERM UMR1037, France, has identified a mechanism by which mutant forms of p27Kip1 that cannot inhibit cyclincyclin-dependent kinase complexes promote cells to take on features of cancer cells. Future studies will determine whether normal p27Kip1 protein can regulate the same mechanism if mislocalized, as it often is in human tumors.

TITLE: p27Kip1 controls cytokinesis via the regulation of citron kinase activation

AUTHOR CONTACT:
Arnaud Besson
INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.
Phone: 33.561556435; Fax: 33.561558109; E-mail: arnaud.besson@inserm.fr.

View this article at: http://www.jci.org/articles/view/60376?key=2721832273bd35b1e9f0


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Contact: Karen Honey
press_releases@the-jci.org
734-546-5242
Journal of Clinical Investigation
Source:Eurekalert

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