Tips from the American Journal of Pathology
Novel Biomarker of Metastatic Bladder Cancer A group led by Dr. Dan Theodorescu at the University of Virginia has identified a novel biomarker for metastatic bladder cancer. They report these findings in the February 2009 issue of The American Journal of Pathology.
Bladder cancer is the fifth most commonly diagnosed cancer in the United States. It commonly spreads to both the lung and the liver. This metastasis significantly increases the risk of the disease; however, little is known about what causes either general or organ-specific metastasis.
Smith et al generated bladder cancer cell lines that specifically metastasized to either the lung or the liver. They then identified genes that were expressed in either the lung- or liver-specific line, as well as expressed genes that were shared between the two lines. One such gene, Laminin V gamma 2 (LAMC2), was upregulated in both lung- and liver-specific cell lines, as well as in human tumors.
Dr. Theodorescu and colleagues "found genes whose expression differed based on the metastatic organ site from which they were derived, but also include a core metastatic signature shared between the sites. Several of these suggest therapeutic targets, and some, such as LAMC2, provide novel insights regarding the different routes of metastasis."
Smith SC, Nicholson B, Nitz M, Frierson, Jr HF, Smolkin M, Hampton G, El-Rifai W, Theodorescu D: Profiling bladder cancer organ site specific metastasis identifies LAMC2 as a novel biomarker of hematogenous dissemination. Am J Pathol 2009, 174:371-379
New Molecular Target for Asthma Therapy
Researchers led by Dr. Sem Phan at the University of Michigan discovered that stem cell factor (SCF) plays a critical role in airway remodeling in asthma. This report can be found in the February 2009 issue of The American Journal of Pathology.
Asthma is a common chronic lung disease where airways constrict in response to either environmental or emotional triggers. Inflammation in the lungs plays a major role in the development of asthma, resulting in changes in the structure of the airways, or airway remodeling. This remodeling is accomplished, in part, through the recruitment of specialized cells, fibroblasts, from the bone marrow.
Dolgachev et al hypothesized that SCF, a molecule that is highly expressed in lungs of asthma patients, was involved in the recruitment of bone marrow-derived fibroblasts in a murine model of asthma. SCF neutralization not only prevented airway remodeling, but also inhibited the migration of bone marrow-derived fibroblasts to the lung.
Dr. Phan and colleagues have "for the first time revealed a novel role for SCF … in airway remodeling that is related to its involvement in the recruitment of bone marrow derived fibroblasts." SCF, therefore, could serve as a new therapeutic target for asthma treatment.
Dolgachev VA, Ullenbruch MR, Lukacs NW, Phan SH: Role of stem cell factor and bone marrow-derived fibroblasts in airway remodeling. Am J Pathol 2009, 174: 390-400
Protein from Staph Infection Causes Lung Injury in Pneumonia
Researchers led by Dr. Pyong Woo Park at Children's Hospital, Harvard Medical School found that Staphlococcus aureus & beta toxin causes lung injury in pneumonia. They report their findings in the February 2009 issue of The American Journal of Pathology.
Staphlococcus aureus, a bacterium frequently found on the skin, is one of the four most common causes of hospital-acquired infections. S. aureus infections range from mild skin infections such as pimples to life-threatening diseases such as pneumonia and meningitis.
Pneumonia caused by Staphlococcus aureus is characterized by severe inflammation that results in lung injury. Hayashida et al found that mice infected with S. aureus deficient in the protein beta-toxin had lower levels of lung injury compared with mice infected with wild-type S. aureus. In addition, S. aureus beta-toxin caused lung injury in normal mice, although not in mice that lacked a specific type of white blood cells, neutrophils.
Dr. Park and colleagues "have uncovered a previously unknown in vivo function of beta-toxin in enhancing lung injury during S. aureus pneumonia. …[Their] data suggest that beta-toxin exaggerates lung injury not through its cytotoxic activity, but through its capacity to enhance neutrophil infiltration."
Hayashida A, Bartlett AH, Foster TJ, Park PW: Staphylococcus aureus beta-toxin Induces Lung Injury through Syndecan-1. Am J Pathol 2009, 174: 509-518
New Treatment for Tough Disease
Dr. John Varga and colleagues at Northwestern University Feinberg School of Medicine found that rosiglitazone, a treatment commonly used in type-2 diabetes, may reduce the severity of scleroderma. These findings are presented in the February 2009 issue of The American Journal of Pathology.
Scleroderma is an autoimmune disease that results in excessive collagen accumulation. People with scleroderma have hardened patches on their skin, and can have heart, kidney, lung, or intestinal damage due to fibrosis.
Peroxisome proliferator activated receptor-gamma (PPAR-gamma) is a protein important in fibrosis. Wu et al therefore examined skin inflammation in a mouse model of scleroderma. They found that treatment with rosiglitazone, a potent PPAR-gamma activator, reduced the symptoms of scleroderma in these mice.
They conclude that their results "indicate that rosiglitazone treatment attenuates inflammation, dermal fibrosis, and subcutaneous lipoatrophy via PPAR-gamma in a mouse model of scleroderma and suggest that pharmacological PPAR-gamma ligands, widely used as insulin sensitizers in the treatment of type-2 diabetes mellitus, may be potential therapies for scleroderma."
Wu M, Melichian DS, Chang E, Warner-Blankenship M, Ghosh AK, Varga J: Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma. Am J Pathol 2009, 174: 519-533
Nerve Signals Contribute to Motor Neuron Death in Amyotropic Lateral Sclerosis (ALS)
A group led by Dr. Lee Martin of Johns Hopkins University School of Medicine discovered that loss of inhibitory neuron signaling may lead to motor neuron cell death in ALS. They present their data in the February 2009 issue of The American Journal of Pathology.
ALS, often referred to as "Lou Gehrig's disease", results in progressive loss of muscle control due to the death of motor neurons, which connect the brain and spinal cord with muscles. There is no current cure or treatment for ALS.
One potential cause of motor neuron death in ALS is hyperexcitability, which occurs when neurons are overactivated. Chang et al proposed that this hyperexcitability could be due in part to loss of inhibition of the neurons. They found that the number of a certain type of inhibitory neurons, glycinergic neurons, was reduced in a mouse model of ALS. Importantly, these neurons were lost before structural evidence of motor neuron degeneration was observed, suggestive a potential causative role.
Drs. Chang and Martin conclude that "selective loss of inhibitory glycinergic interneuron regulation of motoneuron function or glycinergic interneuron degeneration could contribute to motoneuron degeneration in ALS. It remains to be determined if interneuronal loss is due to pathology intrinsic to the interneuron or if it is secondary to very early primary disease in their target motoneurons."
Chang Q, Martin LJ: Glycinergic Innervation of Motoneurons is Deficient in Amyotrophic Lateral Sclerosis Mice: A Quantitative Confocal Analysis. Am J Pathol 2009, 174: 574-585
Breastfeeding May Prevent Breast Cancer
Dr. Michael Lisanti and colleagues at Thomas Jefferson University found that extended lactation protects again mammary tumor development. These findings are presented in the February 2009 issue of The American Journal of Pathology.
Women who breastfeed for greater than two years have a significantly reduced risk of developing breast cancer later in life. It has been difficult to determine the cause of this benefit, however, due to the lack of a suitable animal model of extended lactation.
In this study, Sotgia et al demonstrated that mice deficient in caveolin 3, which is expressed in some mammary cells, had a constitutive lactation phenotype. Notably, caveolin 3-deficient mice were also protected against mammary tumor formation and lung metastases. These mice, therefore, provide a model of constitutive lactation that may be used to study the prevention or treatment of human breast cancers.
Dr. Lisanti's group suggest that "a lactation-based therapeutic strategy would provide a more natural and non-toxic approach to the development of novel anti-cancer therapies. In this regard, targeted reduction of Cav-3 levels in the mammary gland may represent a new therapeutic strategy for preventing the onset of human breast cancers."
Sotgia F, Casimiro MC, Bonuccelli G, Liu M, Menezes DW, Er O, Daumer KM, Mercier I, Witkiewicz AK, Minetti C, Capozza F, Gormley M, Quong AA, Rui H, Frank PG, Milliman JN, Knudsen ES, Zhou J, Wang C, Pestell RG, Lisanti MP: Loss of Caveolin-3 Induces a Lactogenic Microenvironment that is Protective Against Mammary Tumor Formation. Am J Pathol 2009, 174: 613-629
Source: American Journal of Pathology
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