Tips from the American Journal of Pathology

December 30, 2008

Fat Tissue Is Sensitive to Irradiation

Researchers led by Dr. Béatrice Cousin at Institut Louis Bugnard found that irradiation damages fat tissue. They report their findings in the January 2009 issue of The American Journal of Pathology.

Radiation therapy directed at cancer management also damages normal tissues. Autologous transplant of tissues such as fat tissue has often been used to prevent the fibrosis, organ dysfunction, and necrosis that result from radiation treatment; however, the effects of radiation on the transplanted fat tissue had not been studied.

Dr. Cousin's group characterized adipose tissue isolated from mice after total body irradiation. They found that fat pads weighed significantly less post-irradiation and had decreased adipocyte size and a reduced number of mature adipocytes. Poglio et al also observed severe decreases in the number of proliferating cells and increases in the number of dying cells.

Taken together, the data from Dr. Cousin's group suggest that "in terms of therapeutics, these acute affects may modify the reconstructive capacity of adipose tissue and therefore its use in autologous fat tissue transfer after irradiation." These results call into question the effectiveness of transplanting adipose tissue during radiation therapy.

Poglio S, Galvani S, Bour S, André M, Prunet-Marcassus B, Pénicaud L, Casteilla L, Cousin B: Adipose Tissue Sensitivity to Radiation Exposure. Am J Pathol 2009, 174:44-53




CXCL1 Decreases Severity of Multiple Sclerosis-like disease

A group led by Dr. Cedric Raine at Albert Einstein College of Medicine have explored the expression of an immune molecule (CXCL1) that interacts with myelin-producing cells, finding that CXCL1 decreases the severity of disease in a mouse model of multiple sclerosis (MS). They report their data in the January 2009 issue of The American Journal of Pathology.

The autoimmune disease multiple sclerosis (MS) attacks the central nervous system, resulting in demyelination of neurons. Myelin-producing cells in the central nervous system are severely depleted in lesions in patients with MS.

Myelin-producing cells express immune receptors and have been shown to respond to the immune molecule CXCL1, although the role of CXCL1 in MS has not been previously explored. Dr. Raine and colleagues examined the effects of CXCL1 specifically expressed in the nervous system in a mouse model of MS. They observed decreased severity of disease and more prominent remyelination in these mice. CXCL1, therefore, may play a neuroprotective role in CNS autoimmune demyelination.

In future studies, Dr. Raine's group plans to determine how CXCL1 mediates protection in MS. "Exploration of these pathways affords novel therapeutic avenues to enhance the limited remyelination typically seen in MS."

Omari KM, Lutz SE, Santambrogio L, Lira SA, Raine CS: Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1. Am J Pathol 2009, 174:164-176




New Candidate to Prevent Inflammation

Dr. Sonia Oliani and colleagues at São Paulo State University have identified a potential new molecule that inhibits inflammation, receptor for formylated peptides-2 (FPR-2). These findings are presented in the January 2009 issue of The American Journal of Pathology.

Inflammation of the peritoneum is characterized by severe abdominal pain. This inflammation can be prevented by annexin A1, which inhibits the migration of inflammation-inducing white blood cells into the affected area.

In this study, Gastardelo et al examined the identities of the receptors responsible for the anti-inflammatory effects of annexin A1 in a mouse model of peritonitis. FPR family members had been previously shown to interact with annexin A1. Yet FPR-1-deficient mice, unlike annexin A1-null mice, did not have increased white blood cell recruitment. Instead, annexin A1 colocalized with another FPR family member, FPR-2.

The data by Gastardelo et al "provide in vivo evidence that endogenous annexin A1 is an essential mediator for homeostasis during the inflammatory process." They go on to propose "that these experimental findings may impact the development of novel therapeutics based on the anti-migratory actions of annexin A1."

Gastardelo TS, Damazo AS, Dalli J, Flower RJ, Perretti M, Oliani SM: Functional and ultrastrutural analysis of annexin A1 and its receptor in extravasting neurophils during inflammation. Am J Pathol 2009, 174:177-183




Cyclophilin B Is a Possible New Target for Treating Breast Cancer

Dr. Charles Clevenger and colleagues at Northwestern University have uncovered that cyclophilin B may contribute to progression in breast cancer. Their report can be found in the January 2009 issue of The American Journal of Pathology.

The protein cyclophilin B affects cell division, motility, and death, all of which are altered in cancerous cells. To explore the role of cyclophilin B-mediated gene regulation in breast cancer, Dr. Clevenger and colleagues inhibited cyclophilin B expression in breast cancer cells. They found that absence of cyclophilin B impacted 27 different protein networks and decreased cell proliferation, motility, and tumorigenesis. In addition, in human breast tissue, increases in cyclophilin B protein levels correlated with the presence of breast cancer metastases.

The studies by Fang et al "demonstrate that a decrease in cyclophilin B levels ... can profoundly alter the expression of genes and cellular functions relevant to the pathogenesis and progression of breast cancer. In this regard, the development of additional pharmacologic agents that specifically target each of the cyclophilins may have significant utility in the treatment of this disease."

Fang F, Flegler AJ, Du P, Lin S, Clevenger CV: Expression of Cyclophilin B is Associated with Malignant Progression and Regulation of Genes Implicated in the Pathogenesis of Breast Cancer. Am J Pathol 2009, 174:297-308




Inflammation Contributes to Colon Cancer

Researchers led by Dr. Brian Iritani at The University of Washington found that mice that lack the immune inhibitory molecule Smad3 are acutely sensitive to both bacterially-induced inflammation and cancer. They report these findings in the January 2009 issue of The American Journal of Pathology.

Bacteria contribute to the development of certain cancers, in some measure, by stimulating chronic inflammation. Absence of a molecule that inhibits inflammation, Smad3, may therefore increase susceptibility to colon cancer.

To examine whether Smad3 signaling contributes to development of colon cancer, Maggio-Price et al examined mice deficient in Smad3 that lack of adaptive immune responses. They found that these mice are acutely sensitive to bacterially-induced inflammation and cancer due to both deficient T regulatory cell function and increased expression of proinflammatory cytokines. Through increased expression of both pro-oncogenic and anti-apoptotic proteins, epithelial cells in colonic tissues underwent both enhanced proliferation and survival.

"That the inflammatory response to microorganisms is a key event in these results reveals important 'tumor-suppressive' functions for Smad3 in T effector cells, T regulatory cells, and intestinal epithelial cells, all of which may normally limit the development of colon cancer in response to bacterial inflammation," explains Dr. Iritani's group.

Maggio-Price L, Treuting P, Bielefeldt-Ohmann H, Seamons A, Drivdahl R, Zeng W, Lai L-H, Huycke M, Phelps S, Brabb T1, Iritani BM: Bacterial infection of Smad3/Rag2 double-null mice with TGF beta dysregulation as a model for studying inflammation-associated colon cancer. Am J Pathol 2009, 174:317-329
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For press copies of the 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.

American Journal of Pathology

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