Broad Therapy for Muscular Dystrophy
A group led by Dr. Paul T. Martin of The Ohio State University College of Medicine has demonstrated that the glycosyltransferase Galgt2 can lessen symptoms in multiple models of muscular dystrophy. Their report can be found in the July 2009 issue of the American Journal of Pathology.
Muscular dystrophy is a group of inherited muscular disorders that are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue. Recent studies have shown that a number of genes can prevent muscle damage, even though they do not fix the genetic defect that causes the disease. However, these surrogate gene therapies have had limited applicability across different forms of muscular dystrophy.
High expression of the protein Galgt2, which alters the expression and properties of other proteins expressed in skeletal muscle, lessens the symptoms of muscular dystrophy in models with decreased expression of either dystrophin or laminin. Xu et al examined the effects of Galgt2 overexpression in a mouse model of limb girdle muscular dystrophy 2D. Galgt2 overexpression resulted in lower levels of muscle damage, and galgt2 gene therapy protected muscle fibers from injury. Increasing Galgt2 expression may therefore have therapeutic benefits in a broad range of muscular dystrophies.
Dr. Martin and colleagues "have developed [a] gene therapy approach to overexpress the Galgt2 cDNA. …Future work will entail developing methods to allow systemic delivery of such gene therapy vectors using the human Galgt2 cDNA driven by muscle- or muscle/heart-specific promoters. … [They also plan to] identif[y] drugs that would increase [Galgt2] expression in muscle … to stimulate the therapeutic effects of Galgt2 over-expression."
Xu R, DeVries S, Camboni M, Martin PT: Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice. Am J Pathol 2009, 174: 2645-2657
Breast Cancer Prognosis
Dr. Arne Östman and colleagues at the Karolinska Institutet in Stockholm have identified a stromal marker for breast cancer progression. They present these findings in the July 2009 issue of the American Journal of Pathology.
Platelet-derived growth factor (PDGF) receptors are involved in multiple stages of cancer cell growth. However, the contribution of PDGFR expression in the stroma, or surrounding supportive tissue, of the tumor remains unclear.
Paulsson et al therefore characterized PDGFR expression in stroma of various tumors, including lymphoma and colon, ovarian, prostate, lung, and breast cancer. They found highly variable PDGFR expression in solid tumors, with colon and prostate tumors expressing the highest stromal levels of one type of PDGFR, PDGFβR. In breast cancer, stromal PDGFβR expression in pre-menopausal breast cancer patients significantly correlated with negative prognosis. These data highlight the importance of examining stromal as well as malignant cell expression of PDGF receptors in disease prognosis.
Paulsson et al suggest that "the findings in the present study of robust staining procedures for PDGF receptors should motivate continued studies of the response-predicative value of stromal PDGF receptor status."
Paulsson J, Sjöblom T, Micke P, Pontén F, Landberg G, Heldin C-H, Bergh J, Brennan DJ, Jirström K, Östman A: Prognostic significance of stromal PDGF β-receptor expression in human breast cancer. Am J Pathol 2009, 174: 2752-2764
Carbon Monoxide Prevents Clotting
Researchers led by Drs. James F. George and Anupam Agarwal at the University of Alabama at Birmingham have found that carbon monoxide (CO) can protect against arterial clotting. They report their data in the July 2009 issue of the American Journal of Pathology.
Carbon monoxide poisoning is extremely toxic; exposure prevents oxygen delivery to body tissues and is often fatal. However, inflamed or injured tissues upregulate heme oxygenase-1 (HO-1), a protein that both protects cells and produces CO, suggesting that low levels of CO may have protective effects.
To determine if HO-1 and CO can protect against arterial clotting, Chen et al examined clotting mechanisms in mice that received arterial transplants. Absence of HO-1 in these mice resulted in significant mortality due to arterial clotting; however, treatment with a CO-releasing molecule both decreased clotting and improved survival.
Drs. George, Agarwal, and colleagues conclude that HO-1/CO plays an "important role …[in] protection against vascular arterial thrombosis in murine aortic allotransplantation."
Chen B, Guo L, Fan C, Bolisetty S, Joseph R, Wright MM, Agarwal A, George JF: Carbon Monoxide Rescues Heme Oxygenase-1-deficient Mice from Arterial Thrombosis in Allogeneic Aortic Transplantation. Am J Pathol 2009, 174: 2832-2839
Blood Flow in Alzheimer's Disease
Dr. Jennifer C Palmer and colleagues at the University of Bristol have discovered that endothelin converting enzyme-2 (ECE-2) may cause the decrease in cerebral blood flow seen in Alzheimer's disease. These results are presented in the July 2009 issue of the American Journal of Pathology.
Alzheimer's disease is the most common form of dementia. Aβ peptide, which accumulates in the brain of Alzheimer's disease patients, is thought to lead to tightening of the blood vessels and reduction of cerebral blood flood. ECE-2 may contribute to these symptoms by converting an inactive precursor to endothelin-1, which constricts blood vessels.
To determine if ECE-2 affects cerebral blood flow in Alzheimer's disease, Palmer et al examined the expression of ECE-2. They found that ECE-2 levels were elevated in patients with Alzheimer's disease and that Aβ could increase ECE-2 expression in vitro. These data indicate that ECE-2 levels are increased in response to Aβ and may cause the decrease in cerebral blood flow seen in Alzheimer's disease.
Palmer et al "suggest that [endothelin-1] receptor antagonists, already licensed for treating other diseases, could be of benefit in [Alzheimer's disease] therapies."
Palmer JC, Baig S, Kehoe PG, Love S: Endothelin-Converting Enzyme-2 is Increased in Alzheimer's Disease. Am J Pathol 2009, 174: 2672-2680
Expression of Myoglobin in Human Cancers
A group led by Dr. Alberto Bardelli at The University of Turin Medical School reports that myoglobin may protect against the stresses of tumor growth. This study can be found in the July 2009 issue of the American Journal of Pathology.
Myoglobin plays an important role in muscle cells by both transporting oxygen and preventing cell damage by scavenging free radicals. Tumor cells often survive in hypoxic (low oxygen), high free radical environments, despite these stresses on tumor growth.
Flonta et al hypothesized that certain cancers may express myoglobin to survive the conditions associated with tumor growth. Indeed, human epithelial tumors, including breast, lung, ovary, and colon carcinomas, expressed high levels of myoglobin at early stages of development. In addition, myoglobin was induced in cell lines subjected to hypoxia, oxidative stress, and mitogenic stimulation. Myoglobin expression in carcinomas may therefore protect against the stresses of tumor growth.
Dr. Bardelli and colleagues postulate that "should myoglobin prove to play a causative role in tumor progression, … it is tempting to speculate that targeting one or more of its multiple functions by pharmacological agents or more advanced molecular tools could represent a novel therapeutic strategy in oncology."
Flonta SE, Arena S, Pisacane A, Michieli P, Bardelli A: Expression and Functional Regulation of Myoglobin in Epithelial Cancers. Am J Pathol 2009, 174: 2611-2616
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The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.
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