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Notch1 Contributes to Scar Tissue in the Lungs

A group led by Dr. Sem Phan at the University of Michigan, Ann Arbor identified Notch1 as a mediator of lung fibrosis. They present their data in the May 2009 issue of The American Journal of Pathology.

Scar tissue, or fibrosis, can accumulate in the lungs, restricting the flow of oxygen and leading to end-stage lung disease, respiratory failure, and eventually death. An increase in the number of a special type of cells, myofibroblasts, strongly contributes to lung fibrosis.

FIZZ1, a protein found in the lungs, increases the number of myofibroblasts in the lungs. Liu et al hypothesized that Notch1, which regulates cell fate in numerous cell types, plays a role in FIZZ1-mediated myofibroblast differentiation. They found that Notch1 led to an increase of myofibroblasts in the lungs, and that mice that lacked Notch1 had decreased responses to FIZZ1 and lower levels of lung fibrosis.

Taken together, these data suggest that "Notch1 signaling in response to FIZZ1 may play a significant role in myofibroblast differentiation during lung fibrosis." Therefore, Notch1 may provide a novel target for treatment of scar tissue in the lungs.

Liu T, Hu B, Choi YY, Chung MJ, Ullenbruch M, Yu H, Lowe JB, Phan SH: Notch1 signaling in FIZZ1 induction of myofibroblast differentiation. Am J Pathol 2009, 174: 1745-1755

Suppressor of Cytokine Signaling (SOCS)-1 Inhibits Prostate Cancer Growth

Zoran Culig and colleagues at the Innsbruck Medical University, Austria discovered that SOCS-1 negatively regulates prostate cancer proliferation. This report can be found in the May 2009 issue of The American Journal of Pathology.

SOCS family members are expressed in a variety of cancers, including chronic myeloid leukemia, melanoma, and prostate cancer. The role of the various SOCS family members in carcinogenesis, however, may be tissue dependent.

Neuwirt et al identified SOCS-1 expression in multiple prostate cancer cell lines as well as in tissues from prostate cancer patients. They found that SOCS-1 blocks proliferation of prostate cancer cells and that inhibition of SOCS-1 expression stimulated tumor cell growth.

SOCS-1, therefore, plays a negative regulatory role in prostate cancer proliferation. In future studies they will address "other possible aspects of SOCS-1 action in carcinoma of the prostate, such as regulation of the immune response."

Neuwirt H, Puhr M, Santer FR, Susani M, Doppler W, Marcias G, Rauch V, Brugger M, Hobisch A, Kenner L, Culig Z: Suppressor of cytokine signaling (SOCS)-1 is expressed in human prostate cancer and exerts growth-inhibitory function through down-regulation of cyclins and cyclin-dependent kinases. Am J Pathol 2009, 174: 1921-1930

TIP30 Inhibits Lung Cancer Metastasis

Researchers in Shanghai, China suggest that TIP30 prevents metastatic progression of lung cancer. They report these findings in the May 2009 issue of The American Journal of Pathology.

TIP30 is a putative tumor suppressor with decreased expression in numerous cancers including melanoma, breast cancer, and colon cancer. Lung cancer is the most common cancer worldwide, both in terms of incidence and of mortality.

To determine if TIP30 plays a role in lung cancer progression and metastasis, Tong et al examined TIP30 expression in paired cancerous and non-cancerous lung tissue. TIP30 expression was decreased in a third of non-small cell lung cancers compared with normal controls, and reduced TIP30 expression correlated with lymph node metastasis. In addition, inhibition of TIP30 expression promoted lung cancer metastasis and angiogenesis in mice,

Tong et al conclude that "TIP30 may function as a tumor suppressor gene and play important roles in suppressing the progression and metastasis of lung cancer." These findings highlight TIP30 as a potential new therapeutic for metastatic lung cancer.

Tong X, Li K, Luo Z, Lu B, Liu X, Wang T, Pang M, Liang B, Tan M, Wu M, Zhao J, Guo Y: Decreased TIP30 expression promotes tumor metastasis in lung cancer. Am J Pathol 2009, 174: 1931-1939

SPARC (Secreted Protein Acidic and Rich in Cysteine) in Kidney Disease

Amy Sussman and colleagues at the University of Washington, Seattle found that SPARC may contribute to kidney disease. These findings are presented in the May 2009 issue of The American Journal of Pathology.

Chronic kidney disease is associated with significant injury and loss of podocytes, which are cells crucial for filtering the blood of toxins. SPARC, a counter-adhesive protein, is upregulated in podocytes upon injury.

To define the role of SPARC in kidney disease, Sussman et al examined immune-mediated kidney disease in mice deficient in SPARC as well as in normal mice. They found that hardening of the kidney was reduced in SPARC-null mice compared with normal controls, in part due to maintenance of podocytes. In addition, SPARC-deficient podocytes were more resistant to stress-induced detachment.

Sussman et al "have established a causal role for SPARC in the progression of glomerular disease following immune-mediated injury of the podocyte. [These] findings support a causal role for induction of the matricellular protein SPARC in mediating podocyte loss, thereby accelerating [kidney] injury."

Sussman AN, Sun T, Krofft RM, Durvasula RV: SPARC accelerates disease progression in experimental crescentic glomerulonephritis. Am J Pathol 2009, 174: 1827-1836

Gangliosides May Protect Against Parkinson's Disease

Researchers at the Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan established the mechanism by which gangliosides may help treat Parkinson's disease. These data are presented in the May 2009 issue of The American Journal of Pathology.

Parkinson's disease is caused by a loss of dopamine-secreting cells in the brain, which results in impaired motor skills, speech, and other functions. Abnormal accumulation of the protein α-synuclein may contribute to this neuronal cell death.

Gangliosides have been shown to inhibit a-synuclein aggregation. To discover the mechanism that drives ganglioside-mediated protection from a-synuclein-caused cell death, Wei et al treated cells with a molecule that disrupts the function of lysosomes, cell components responsible for digesting unneeded and excess material in cells. Treatment with gangliosides reversed the lysosomal disruption, which suggests that gangliosides protect against the lysosomal damage of a-synuclein accumulation.

Based on their present result, Wei et al "speculate that deregulation of the expression of gangliosides may underlie the process of axonal degeneration. If this is the case, it is naturally expected that restoration of the protective action of gangliosides might be a useful therapeutic strategy."

Wei J, Fujita M, Nakai M, Waragai M, Sekigawa A, Sugama S, Takenouchi T, Masliah M, Hashimoto M: Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am J Pathol 2009, 174: 1891-1909


Contact: Angela Colmone
American Journal of Pathology

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