Tips from the American Journal of Pathology

A group led by Dr. Jian-xing Ma at The University of Oklahoma Health Sciences Center, Oklahoma City, OK has demonstrated that the Wnt signaling pathway plays a role in diabetic retinopathy. Their report can be found in the December 2009 issue of The American Journal of Pathology.

Diabetic retinopathy, damage to the retina in the eye as a result of inflammatory complications of diabetes mellitus, affects up to 80% of all patients who have had diabetes for 10 years or more. Diabetic retinopathy is the leading cause of blindness in the working age population; however, the mechanisms by which diabetes induces this inflammation remain unclear.

To determine if the Wnt signaling pathway, which is activated under numerous pathological conditions, plays a role in diabetic retinopathy, Chen et al examined retinal expression and activation of a Wnt signaling molecule in human patients with diabetic retinopathy as well as in mouse models. They found high retinal expression and activation of Wnt signaling molecules in patients with diabetic retinopathy. Moreover, blocking Wnt signaling decreased the severity of diabetic retinopathy in mouse models. Wnt therefore provides a new target for diabetic retinopathy therapy.

Taken together, the data by Dr. Ma and colleagues suggest that "Wnt pathway activation is a novel pathogenic mechanism for [diabetic retinopathy] in both human patients and in animal models. Thus, the Wnt pathway represents a new target for pharmaceutical intervention of [diabetic retinopathy]."

Chen Y, Hu Y, Zhou T, Zhou KK, Mott R, Wu M, Boulton M, Lyons TJ, Gao G, Ma J: Activation of the Wnt Pathway Plays a Pathogenic Role in Diabetic Retinopathy in Humans and Animal Models. Am J Pathol 2009, 175: 2676-2685

Dr. Carme Espinet and colleagues at the University of Lleida, Lleida, Spain have discovered that a precursor to nerve growth factor (pro-NGF) may play a pathogenic role in Alzheimer disease. They present these findings in the December 2009 issue of The American Journal of Pathology.

Alzheimer disease is a degenerative, terminal form of dementia that affects over 35 million people world-wide. Oxidative stress, which occurs in the early stages of Alzheimer disease, may modify molecules, resulting in loss or alteration of their function.

A precursor to nerve growth factor (pro-NGF) is expressed at high levels in Alzheimer disease-affected individuals, and accumulation of pro-NGF may lead to neural cell death. Kichev et al showed that pro-NGF is modified in an Alzheimer disease stage-dependent manner by oxidative stress and that modified pro-NGF blocked processing to mature NGF and led to neuronal cell death. Furthermore, injection of modified pro-NGF or pro-NGF derived from human Alzheimer disease patients into mice resulted in cognitive and learning impairment, suggesting that modified pro-NGF may provide a novel pathogenic pathway for Alzheimer disease.

Dr. Espinet's group suggests "that intra-cerebroventricular administration of AGE/ALEs modified pro-NGF to mice impairs learning tasks, thus reinforcing the idea that pro-NGF could have a relevant role in the ethiopathogenesis of the disease."

Kichev A, Ilieva EV, Piñol-Ripoll G, Podlesniy P, Ferrer I, Portero-Otín M, Pamplona R, Espinet C: Cell death and learning impairment in mice caused by in vitro modified pro-NGF can be related to its increased oxidative modifications in Alzheimer disease. Am J Pathol 2009, 175: 2574-2585

Dr. Kyoko Hida and colleagues at Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan and Harvard Medical School in Boston, MA have found that endothelial cells associated with tumors have cytogenetic abnormalities. They report their data in the December 2009 issue of The American Journal of Pathology.

Angiogenesis, or the growth of new blood vessels, plays a key role in tumor spread and metastasis. The endothelial cells that comprise tumor-associated blood vessels have previously been thought to be genetically stable, but recent evidence has been provided for abnormal copies of chromosomes in vascular endothelial cells in some tumor types.

Akin et al hypothesized that endothelial cells associated with human renal cell carcinoma would have cytogenetic abnormalities. They found that a portion of tumor-associated endothelial cells had aneuploidy, an abnormal number of chromosomes, and that many of these cells had stem cell-like characteristics. Abnormal endothelial cells may therefore contribute to the pathogenesis of metastatic carcinoma.

Dr. Akin and colleagues conclude that "aneuploid [tumor-assoicated endothelial cells] that organize tumor tissue surrounding the stroma might affect tumor progression and metastasis. It will be important to target abnormal tumor stroma in order to develop more effective cancer therapies."

Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda N, Akiyama K, Harabayashi T, Shinohara N, Nonomura K, Klagsbrun M, Shindoh M: Cytogenetic Abnormalities of Tumor-Associated Endothelial Cells in Human Malignant Tumors. Am J Pathol 2009, 175: 2657-2667

Researchers from the Keio University, School of Medicine, Tokyo, Japan have discovered that epithelial-mesenchymal transition (EMT) plays a role in damage in the eye after bone marrow transplantation. These results are presented in the December 2009 issue of The American Journal of Pathology.

After bone marrow transplantation, transplanted immune cells can recognize the graft recipient as foreign (similar to how the immune system recognizes bacteria as foreign), resulting in an attack on host tissues. When this attack occurs in the eye, it may lead to vision loss and excessive fibrosis.

EMT, which is characterized by a change in cells from adherent to mobile, has been implicated in fibrotic diseases. Ogawa et al therefore explored the potential role of EMT in eye disease following bone marrow transplantation. They observed several features of EMT in eyes after bone marrow transplantation including down-regulation of adhesion molecules and up-regulation of EMT markers in epithelial cells. These results indicate that EMT may be at least partially responsible for fibrotic eye damage in patients following bone marrow transplantation.

Ogawa et al suggest that "a full understanding of the contribution of different extracellular triggers in … fibrosis [in the eye] will elucidate the mechanism of the dynamic process of EMT [in transplanted cell attack on the new host] and improve the quality of life of patients [after bone marrow transplantation]."

Ogawa Y, Shimmura S, Kawakita T, Yoshida S, Kawakami Y, Tsubota K: Epithelial Mesenchymal Transition in Human Ocular Chronic Graft-Versus-Host Disease. Am J Pathol 2009, 175: 2372-2381

For press copies of these articles, please contact Dr. Angela Colmone at 301-634-7953 or acolmone@asip.org.

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.