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Tips from the American Journal of Pathology
Date:8/26/2009

New Target for Treating Breast Cancer Metastasis

Dr. Amanda Harvey and colleagues at Brunel University have demonstrated that the protein Brk plays a role in breast cancer progression and dissemination. Their report can be found in the September 2009 issue of the American Journal of Pathology.

Breast cancer metastasis causes nearly 90% of the lethality among breast cancer patients. Non-metastatic breast cancer cells rely on interactions with other cells and the extracellular matrix to survive. Metastatic breast cancer cells must survive in the absence of these interactions.

Harvey et al hypothesized that Brk, a tyrosine kinase expressed predominantly in breast tumors compared with normal breast tissue, plays a role in breast cancer progression by promoting anchorage independence. Indeed, high-grade tumors from human breast cancer patients expressed elevated levels of Brk when compared with lower grade tumors. Inhibiting Brk expression resulted in cell death in the absence of cell-cell and cell-matrix interactions, and tumor cells with increased levels of Brk expression survived without these interactions. These data therefore support a role for Brk in breast cancer progression and dissemination.

Dr. Harvey and colleagues suggest "that Brk plays a role in protecting breast cancer cells from detachment-induced cell death. Therefore, Brk expression in carcinomas may confer a survival advantage on metastasizing tumor cells. [Future studies will examine] whether this function is manifest in other Brk-positive tumor cells from tissues other than the breast, such as the colon and prostate."

Harvey AJ, Pennington CJ, Porter S, Burmi RS, Edwards DR, Court W, Eccles SA, Crompton MR: Brk protects breast cancer cells from autophagic cell death induced by loss of anchorage. Am J Pathol 2009, 175: 1226-1234

Wnk1 is Critical in Angiogenesis and Heart Development

A group led by Dr. Chou-long Huang at the University of Texas Southwestern Medical Center in Dallas, Texas have discovered that the protein Wnk1 (with-no-lysine (K)-1) is critical in angiogenesis and heart development. They present these findings in the September 2009 issue of the American Journal of Pathology.

Angiogenesis is the formation of blood vessels in organs. However, the molecular mechanisms that regulate blood vessel and heart development, particularly the differentiation of arteries and veins, remain unclear.

Wnk1 is required for normal development; yet, its role in vascular development remains poorly characterized. Xie et al therefore examined cardiovascular development in mice that did not express Wnk1. These Wnk1-null mice displayed defective heart development. In addition, Wnk1-deficiency resulted in an angiogenic defect in blood vessels, with altered expression of markers of both arteries and veins. These defects were specific to endothelial Wnk1 expression. Thus, endothelial Wnk1 is critical for angiogenesis and cardiac development and may contribute to arterial-venous differentiation.

This study by Xie et al "provide[s] strong evidence suggesting that function of WNK1 in endothelial cells defines a novel pathway or mechanism in the determination and/or maintenance of arterial-venous identity and is essential for embryonic cardiac development."

Xie J, Wu T, Xu K, Huang IK, Cleaver O, Huang C-l: Endothelial-specific Expression of WNK1 Kinase Is Essential for Angiogenesis and Heart Development in Mice. Am J Pathol 2009, 175: 1315-1327

Drug Abuse Worsens HIV-Associated Neurocognitive Disorders (HANDs)

Researchers led by Dr. Joan Berman at the Albert Einstein School of Medicine in New York, NY have found that drug abuse increases the severity of HANDs through dopamine signaling. They report their data in the September 2009 issue of the American Journal of Pathology.

HANDs is a neurocognitive disease that leads to motor dysfunction, speech problems, and behavioral changes. It is caused by HIV-infected white blood cells (macrophages) in the central nervous system, which cause inflammation that leads to neural damage. The use of illicit drugs such as cocaine and methamphetamine increase the symptoms of HANDs.

To examine the mechanisms underlying drug abuse-mediated enhancement of HANDs, Gaskill et al examined the effects of the neurotransmitter dopamine, which is induced by abused drugs, on HIV infection in macrophages. Macrophages expressed dopamine receptors 1 and 2 and were activated upon dopamine signaling. Signaling through dopamine receptor 2 increased the total number of HIV-infected macrophages, resulting in an increase in HIV replication. Therefore, drug abuse could exacerbate HANDs through a common increase in neural dopamine levels.

Dr. Berman and colleagues conclude that "macrophages, and particularly macrophage [dopamine] receptors, may provide targets for intervention that might slow the development of neurological disease in HIV positive individuals using [dopamine]-enhancing substances. Overall, these findings provide new avenues of investigation of macrophage functions as well as potential therapeutic targets to delay or prevent the acceleration of HAND and other HIV-related pathologies enhanced by drug abuse."

Gaskill PJ, Calderon TM, Luers AJ, Eugenin EA, Javitch JA, Berman JW: HIV infection of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse. Am J Pathol 2009, 175: 1148-1159

Signaling Molecule Key in Atrial Fibrillation

Dr. Julie McMullen and colleagues at Baker IDI Heart and Diabetes Institute, Melbourne Australian have discovered that PI3K (p110α) plays a role in atrial fibrillation. These results are presented in the September 2009 issue of the American Journal of Pathology.

Atrial fibrillation, which is characterized by uncoordinated activation of the atria in the heart, can cause heart failure, stroke, and thromboembolism. Inhibition of PI3K (p110α), a critical molecular signal for insulin, is associated with risk factors for atrial fibrillation, including aging, obesity, and diabetes.

To determine if PI3K (p110α) plays a role in atrial fibrillation, Pretorius et al examined a mouse model of dilated cardiomyopathy, where the heart becomes weak and large and cannot pump blood efficiently, with decreased levels of PI3K (p110α) expression. These mice developed atrial fibrillation and had depressed cardiac function, but increasing PI3K activity reduced the severity of these symptoms. Human patients with atrial fibrillation were found to have decreased levels of PI3K activity as well. Strategies to activate PI3K (p110α) may therefore prove to be new treatment options for atrial fibrillation and heart failure.

Pretorius et al "have developed a genetic mouse model of [atrial fibrillation] that is associated with heart failure and overt atrial remodelling, simulating the clinical situation. A reduction in PI3K(p110α) activity, a critical effector of insulin signaling, can help explain the link between risk factors such as aging, obesity and diabetes with [atrial fibrillation]. Strategies/agents that can activate PI3K(p110α) specifically in the heart may represent a therapeutic approach for heart failure and [atrial fibrillation]."

Pretorius L, Du X-J, Woodcock EA, Kiriazis H, Lin RCY, Marasco S, Medcalf RL, Ming Z, Head GA, Tan JW, Cemerlang N, Sadoshima J, Shioi T, Izumo S, Lukoshkova E, Dart AM, Jennings GL, McMullen JR: Reduced phosphoinositide 3-kinase (p110α) activation increases the susceptibility to atrial fibrillation. Am J Pathol 2009, 175: 998-1008

CD8+ T Cells Cause Collateral Bystander Damage

A group led by Dr. Norbert Goebels of the University Hospital Zrich in Zrich, Switzerland reports that CD8+ T cells damage myelinated axons in a mouse model of multiple sclerosis (MS). This study can be found in the September 2009 issue of the American Journal of Pathology.

Demylination and axonal damage cause the cognitive and motor symptoms of MS. Although the immune system, in particular CD8+ T cells, contributes to this axonal damage, it remains unclear whether this damage results from direct attack of the axons or as an indirect byproduct (collateral bystander damage).

Sobottka et al used a live continuous confocal imaging approach to examine the role of CD8+ T cells in experimental autoimmune encephalitis (EAE), a mouse model of MS. They found that CD8+ T cells damaged myelinated axons, even when the stimulatory antigen was expressed inside but not on the surface of nearby oligodendrocytes, which produce the myelin that protects the axons from damage. Thus, axonal loss can be the result of "collateral bystander damage," and new treatments should be developed with a focus on the CD8+ T cell/oligodendrocyte interface.

Dr. Goebels and colleagues "are confident that [these] findings critically contribute to the understanding of CD8-mediated neuropathology in CNS inflammation, strengthen a pathogenic role of CD8+ T cells in MS and advocate for the development of future immunotherapies aiming at the CD8-myelin/oligodendrocyte interface."

Sobottka B, Harrer MD, Ziegler U, Fischer K, Hnig T, Becher B, Goebels N: Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss. Am J Pathol 2009, 175: 1160-1166


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Contact: Angela Colmone
acolmone@asip.org
301-634-7953
American Journal of Pathology
Source:Eurekalert

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