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Stromal Caveolin-1 Predicts Breast Cancer Prognosis

Two articles in the June 2009 issue of the American Journal of Pathology demonstrate the role of stromal caveolin-1 expression as a prognostic marker for breast cancer progression. These articles are highlighted by an accompanying Commentary.

Caveolin-1, a protein that functions in endocytosis and signal transduction, plays a major role in breast cancer tumorigenesis. However, although calveolin-1 expression has been extensively studied in epithelial cells in breast cancer patients, the value of epithelial caveolin-1 as a prognostic marker has been limited.

Witkiewicz et al and Sloan et al therefore examined caveolin-1 expression in the stromal microenvironment of human breast cancer. Stromal expression of caveolin-1 correlated with reduced levels of metastasis, and caveolin-1 was not expressed in stroma of patients with poor clinical outcome. In addition, tumor onset in mice was accelerated in the absence of stromal caveolin-1. Caveolin-1 may therefore function as a tumor suppressor in the stromal microenvironment and serve as a new prognostic marker for breast cancer progression.

Dr. Mina Bissell, who is not associated with these studies, suggests that "for now, the two studies presented in this issue of the AJP provide additional validation that the microenvironment is an important and potentially powerful source of clinical information to predict patient outcome, and demonstrate specifically that stromal Cav-1 may be a valuable clinical marker. Determining whether stromal Cav-1 functions to directly suppress tumor growth, and uncovering the factors which regulate its expression, may also reveal novel therapeutic avenues."

Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, Kleer CG, Brody JR, Lisanti MP: An Absence of Stromal Caveolin-1 Expression Predicts Early Tumor Recurrence and Poor Clinical Outcome in Human Breast Cancers. Am J Pathol 2009, 174: 2023-2034

Sloan EK, Ciocca DR, Pouliot N, Natoli A, Restall C, Henderson MA, Fanelli MA, Cuello-Carrion FD, Gago FE, Anderson RL: Stromal Cell Expression of Caveolin-1 Predicts Outcome in Breast Cancer. Am J Pathol 2009, 174: 2035-2043

Ghajar CM, Meier R, Bissell MJ: Quis Custodiet Ipsos Custodies: Who Watches the Watchmen? Am J Pathol 2009, 174: 1996-1999

Novel Markers for Kidney Disease Progression

A group led by Drs. Erwin P. Bttinger of the Mount Sinai School of Medicine and Matthias Kretzler at the University of Michigan have established novel markers of kidney disease progression. Their report can be found in the June 2009 issue of the American Journal of Pathology.

Chronic kidney disease may affect up to 16.8% of the US population. Only a minority of patients with chronic kidney disease progress to end-stage renal disease. However, current clinical markers are not sufficient to reliably predict chronic kidney disease progression, which would allow for targeted treatment of high-risk patients.

To identify markers of chronic kidney disease progression, Ju et al screened a mouse model of progressive renal disease to identify genes whose expression correlated with renal disease severity. They then examined human versions of these genes, and found that a subset of these candidates were associated with disease progression and glomerular filtration rate in human patients.

The biomarkers identified by Dr. Bttinger, Dr. Kretzler, and colleagues "predict progressive renal fibrosis in mice and may [therefore] be useful molecular predictors of [chronic kidney disease] progression in humans."

Ju W, Eichinger F, Bitzer M, Oh J, McWeeney S, Berthier CC, Shedden K, Cohen CD, Henger A, Krick S, Kopp JB, Stoeckert Jr. CJ, Dikman S, Schrppel B, Thomas DB, Schlondorff D, Kretzler M, Bttinger EP: Renal Gene and Protein Expression Signatures for Prediction of Kidney Disease Progression. Am J Pathol 2009, 174: 2073-2085

Treatment for Oxygen Toxicity

Dr. Marieke van Zoelen and colleagues at The University of Amsterdam have identified a therapeutic target for preventing oxygen toxicity. They present these findings in the June 2009 issue of the American Journal of Pathology.

Breathing molecular oxygen at high pressures may cause oxygen toxicity, which is characterized by cell death in the central nervous system, lung, and eye. Patients on high concentrations of supplemental oxygen due to respiratory failure or premature birth, people undergoing hyperbaric oxygen therapies, scuba divers, and astronauts are all at risk for oxygen toxicity.

Van Zoelen et al hypothesized that uPAR, which attracts immune cells, plays a role in oxygen toxicity in the lungs. They found that mice treated with high levels of oxygen had an increased number of uPAR-expressing immune cells in their lungs and that mice that lacked uPAR expression had less lung injury.

This work suggests that "inhibition of uPAR may be a novel strategy to reduce the lung injury that accompanies oxygen therapy."

van Zoelen MAD, Florquin S, de Beer R, Pater JM, Verstege MI, Meijers JCM, van der Poll T: Urokinase plasminogen activator receptor-deficient mice demonstrate reduced hyperoxia-induced lung injury. Am J Pathol 2009, 174: 2182-2189

AM80 Blocks Early Multiple Sclerosis

Researchers led by Drs. Takahashi Yamamura and Shinji Oki at the National Institute of Neuroscience, Tokyo, Japan have found that the synthetic retinoid AM80 is effective in treating early symptoms in a mouse model of multiple sclerosis (MS). They report their data in the June 2009 issue of the American Journal of Pathology.

MS is a disease where the immune system attacks the central nervous system, preventing communication between nerve cells in the brain and the spinal cord. A certain type of immune cell, Th17 T cells, plays a pathogenic role in MS and other autoimmune diseases.

Using a mouse model of MS, Klenmann et al found that AM80, a synthetic molecule related to vitamin A, inhibited Th17 T cell function without generating general immunosuppression. AM80 treatment was effective in inhibiting early symptoms in the MS mouse model, even if administered after disease initiation, but it did not prevent chronic symptoms.

Drs. Yamamura, Oki, and colleagues "conclude that treatment with the synthetic retinoid AM80 is a considerable intervention strategy for the acute phase of Th17-mediated autoimmune diseases such as MS."

Klemann C, Raveney BJE, Klemann AK, Ozawa T, von Hrsten S, Shudo K, Oki S, Yamamura T: Synthetic retinoid AM80 inhibits Th17 cells and ameliorates EAE. Am J Pathol 2009, 174: 2234-2245

Repair After Eye Injury

Drs. Sandrine Joly, Charlotte Rem, and colleagues have discovered that both resident and circulating cells remove damaged cells after eye injury. These results are presented in the June 2009 issue of the American Journal of Pathology.

The eyes, like the brain, are an immune-privileged site; the so called blood-retinal barrier limits access of immune cells to the eyes. After eye damage, however, immune cells remove damaged cells.

To locate the source of the immune cells that respond to retinal injury, Joly et al used a mouse model of light-induced photodamage. They found that both resident and circulating (from the bone marrow) immune cells were involved in removal of dead retinal cells. The circulating cells entered the eye without damaging the blood-retinal barrier, and both circulating and resident immune cells entered the blood stream after removing the dead cells.

Joly et al suggest that this process may "enable an immunization against retinal proteins. Specific retinal proteins have long been used to induce ocular autoimmune inflammation. Future studies need to elucidate the potential for autoimmune reactions after injury leading to or enhancing retinal degenerations."

Joly S, Francke M, Ulbricht E, Beck S, Seeliger M, Hirrlinger P, Hirrlinger J, Lang K, Zinkernagel M, Odermatt B, Samardzija M, Reichenbach A, Grimm C, Rem C: Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions. Am J Pathol 2009, 174: 2310-2323


Contact: Angela Colmone
American Journal of Pathology

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