Misregulation of SPAK protein may contribute to B-cell lymphoma development

American Journal of PathologySep 28 2009

A group led by Dr. Michael Teitell at UCLA has demonstrated that misregulation of the protein SPAK may contribute to B-cell lymphoma development. Their report can be found in the October 2009 issue of the American Journal of Pathology.

B-cell lymphomas are the most frequent human immune system cancers. Epigenetic changes, such as DNA hypermethylation, may promote B-cell transformation by silencing tumor suppressor genes.

Expression levels SPAK, a protein that regulates cellular stress responses, are reduced during cancer progression. Using a mouse model of B-cell malignancies and human B-cell lymphoma tissue samples, Balatoni et al report that SPAK expression is inhibited in B-cell tumors due in part to hypermethylation. Decreased SPAK expression protected B cells from environmental stressors that would induce cell death in non-cancerous cells. This SPAK-silenced protection may therefore be responsible for survival and metastatic progression in DNA-damaged B cells.

Dr. Teitell and colleagues suggest "that SPAK silencing in B-cell lymphomas promotes cancer progression by crippling genotoxic stress signaling to impair caspase activation. These results likely generalize to breast, prostate, and possibly other cancers beyond B lymphoma and uncover a novel role for SPAK in controlling the DNA damage response, highlighting a protective cell death mechanism that is disabled during the progression of cancer. SPAK expression or repression may also help indicate those patient tumors that should or should not receive genotoxic therapies as the development of personalized medicine pushes ahead."

Gou Young Koh and colleagues at the Korea Advanced Institute of Science and Technology in Daejeon, Korea have discovered that macrophages, a type of immune cell, impair fluid drainage during peritoneal inflammation. They present these findings in the October 2009 issue of the American Journal of Pathology.

Lymphatic vessels in the diaphragm are responsible for draining excess peritoneal fluid, which lubricates most of the organs in the abdomen. During peritoneal inflammation, however, these vessels have altered structure and function.

To characterize changes in lymphatic vessels during peritoneal inflammation, Kim et al injected the inflammatory molecule LPS into mice to induce peritonitis. LPS injection induced changes in lymphatic vessel structure and function that were reversible upon discontinuation of LPS-induced inflammation. Macrophage migration to these sites of lymphangiogenesis contributed to lymphatic remodeling, and both macrophage attachment to the lymphatic vessels and inflammatory fibrosis resulted in impaired peritoneal fluid drainage. These data highlight the key role of macrophages in inflammation-induced lymphangiogenesis and lymphatic vessel dysfunction in the diaphragm.

This study by Kim et al "reveal[s] that CD11b+ macrophages play an important role in intraperitoneal LPS-induced aberrant lymphangiogenesis and lymphatic dysfunction in the diaphragm." They suggest that "it is possible that human patients with Gram-negative bacterial peritonitis may also have dysfunctional lymphangiogenesis and lymphatic remodeling in the diaphragm."

Researchers led by Drs. Elena Deryugina and James Quigley of The Scripts Research Institute in La Jolla, CA have found that urokine plasminogen activator (uPA) may be instrumental in the early stages of metastasis. They report their data in the October 2009 issue of the American Journal of Pathology.

Prostate cancer, which develops most frequently in men over fifty, is the most common type of cancer of men in the United States. Most prostate cancer-related deaths are due to advanced disease, which often results in metastatic spread to other organs.

Tumor cell intravasation, the entry of aggressive cells into the blood vessels, is an early step in the complex metastatic process. To explore the mechanisms governing intravasation, Conn et al isolated high and low dissemination variants of a prostate carcinoma cell line. The cell line more prone to dissemination had increased angiogenic potential, and these cells were more migratory and invasive. Highly metastatic cells also produced more of the serine protease uPA. By inhibiting uPA activation, invasion, angiogenesis, and intravasation were all blocked.

Drs. Deryugina, Quigley, and colleagues conclude that "a comparative analysis of these congenic variants has indicated important functional roles for VEGF secretion and uPA activation in facilitating tumor cell intravasation and has indicated a potential direct link between tumor-induced angiogenesis and tumor cell intravasation."

AF Protects against Atherosclerosis

Dr. Dorian Haskard and colleagues at the Imperial College, London, UK have discovered that decay accelerating factor (DAF) protects against atherosclerosis. These results are presented in the October 2009 issue of the American Journal of Pathology.

Atherosclerosis describes any hardening and loss of elasticity of the arteries due to a build-up of fatty material such as cholesterol. Activation of the complement system, which consists of a cascade of small proteins that can result in cell lysis or trigger inflammation, plays a regulatory role in atherosclerotic lesion development. However, whereas proximal members of the complement pathway have a protective role, distal components are atherogenic.

DAF regulates complement activation at the C3 (proximal) level, but its role in atherosclerotic lesion development remains unclear. Leung et al hypothesized that DAF plays a protective role in atherosclerosis. Using a DAF-deficient mouse model of atherosclerosis, they found that DAF-deficient animals had increased levels of the distal complement components C5b-9 in aortic lesions. Lesions in DAF-deficient mice had accelerated development and increased size and complexity compared with normal animals. DAF, therefore, plays an essential regulatory role in limiting complement activation on the arterial wall and is protective against atherosclerosis.

This study by Leung et al "underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement."

A group led by Dr. Thomas Bugge of the National Institutes of Health in Bethesda, MD reports that the serum protease matripase is required for global homeostasis of diverse epithelial tissues. This study can be found in the October 2009 issue of the American Journal of Pathology.

Epithelial cells line the surfaces of cavities and structures throughout the body. These cells have multiple general and organ-specific functions, including maintaining ion gradients, transporting molecules, secreting hormones and growth factors, and excluding pathogens.

The serum protease matripase plays a critical role in the function of epithelial cells in the skin; however, matripase is broadly expressed in different types of epithelial tissues. To explore the role of matripase on other epithelial tissues, List et al generated matripase-deficient mice. The loss of matripase was associated with severe organ dysfunction in multiple tissues; these epithelial tissues lost key epithelial functions.

The data by Dr. Bugge and colleagues "all strongly argue for a primary role of matriptase in tissue homeostasis, rather than a role in the restoration of homeostasis after chance injury to epithelial tissues. - This study has revealed an essential role of matriptase in the maintenance of global epithelial homeostasis in the mouse and has provided an important animal model for the further exploration of matriptase function in multiple physiological and pathological processes."