From Science Daily website (see original article)
ScienceDaily (Sep. 24, 2012) — Michigan State University
researchers have unlocked secrets in bone marrow that could lead to
improved treatments for colitis and Crohn's disease.
The results, featured in the current issue of Proceedings of the National Academy of the Sciences,
show that the havoc inflammatory bowel diseases wreaks on the digestive
tract is mirrored in bone marrow. Early indications also show that the
disorders of the gut could potentially be treated through the bone
marrow, said Pam Fraker, MSU University Distinguished Professor of
biochemistry and molecular biology.
"It's possible that if we
could reduce bone marrow's ability to produce inflammatory cells that we
could reduce the severity of colitis and Crohn's disease," said Fraker,
who co-authored the study with MSU colleagues Laura McCabe, professor
of physiology and radiology, and Mark Trottier, research specialist.
"This could limit the damage that the disease causes and reduce the
number of patients needing surgery."
Colitis and Crohn's affect
more than a million people in the United States, including a growing
number of children. There are no preventive treatments; however,
steroids are often prescribed to reduce the diseases' pain and
inflammation. The side effect of this course is tissue damage, which
could lead to surgery and additional complications.
Watching a young patient suffer through the pain of severe colitis bolstered Fraker's need to research this devastating disease.
"She
was very frail, sick, addicted to narcotics to numb her pain and had
several intestinal surgeries to no avail," Fraker said. "This became a
huge motivator for me as it drove home how little real help is available
to these patients."
Fraker focused on bone marrow, which is a
large, highly active and responsive tissue. When colitis was induced in
mice, she was surprised by the significant and swift changes that
occurred in their bone marrow.
The symptoms of colitis, such as
swelling, anemia and unhealthy increases in monocytes and neutrophils,
(cells that fight infection but exacerbate the excessive swelling in
intestines) were reflected in the bone marrow.
The bone marrow's
reactions actually fan the flames of the inflammatory bowel diseases
rather than help cure it. When bone marrow amps up production of
monocytes and neutrophils, it does it at the expense of making
lymphocytes and red blood cells, keys to immune defense.
The research was funded in part by the Crohn's and Colitis Foundation.
giovedì 15 novembre 2012
How Chronic Inflammation Can Cause Cancer
From Science Daily website (see original article)
ScienceDaily (Nov. 12, 2012) - A hormone-like substance produced by the body to promote inflammation can cause an aggressive form of leukemia when present at high levels, according to a new study by researchers at the Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James).
The study shows that high levels of interleukin-15 (IL-15) alone can cause large granular lymphocytic (LGL) leukemia, a rare and usually fatal form of cancer, in an animal model. The researchers also developed a treatment for the leukemia that showed no discernible side effects in the animal model.
Published in the journal Cancer Cell, the findings show that IL-15 is also overexpressed in patients with LGL leukemia and that it causes similar cellular changes, suggesting that the treatment should also benefit people with the malignancy.
"We know that inflammation can cause cancer, but we don't know the exact mechanism," says principal investigator Dr. Michael A. Caligiuri, CEO of The James Cancer Hospital and Solove Research Institute, and director of Ohio State's Comprehensive Cancer Center.
"Here, we show one way it can happen, and we used that information to potentially cure the cancer."
Normally, the body releases IL-15 to stimulate the development, survival and proliferation of natural-killer cells, which are immune cells that destroy cancer and virus-infected cells. This research shows that when IL-15 is present in high amounts in the body for prolonged periods, such as during chronic inflammation, it can cause certain immune cells called large granular lymphocytes, or LGLs, to become cancerous.
This malignant transformation begins when IL-15 attaches to receptors on the surface of normal LGLs, an event that boosts levels of a cancer-causing protein called Myc (pronounced "mick") inside the cells. The high Myc levels, in turn, bring changes that cause chromosome instability and additional gene mutations. The high Myc levels also activate a process called DNA methylation, which turns off a variety of genes, including important genes that normally suppress cancer growth.
"We stand the best chance of curing cancer when we understand its causes," says first author Anjali Mishra, a postdoctoral researcher in Caligiuri's laboratory. "Once we understood how this inflammatory hormone causes this leukemia, we used that information to develop a treatment by interfering with the process."
Caligiuri and Mishra were joined in this study by Dr. Guido Marcucci, associate director for Translational Research at the OSUCCC -- James, Dr. Robert Lee, professor of pharmaceutics and pharmaceutical chemistry in Ohio State's College of Pharmacy and a group of collaborators. The investigators conducted the research using cells isolated from patients with LGL leukemia and a mouse model of the disease. Key findings include:
- Exposing normal, human, large granular lymphocytes to IL-15 caused cell proliferation, chromosomal instability and global DNA hypermethylation;
- Excessive IL-15 activated the cancer-causing Myc oncogene in large granular lymphocytes, leading to genetic instability, DNA hypermethylation and malignant transformation;
- Details of how Myc upregulation causes the genetic instability and hypermethylation.
"We now plan to develop this drug for clinical use," says Marcucci, who holds the John B. and Jane T. McCoy Chair in Cancer Research in Cancer Research.
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