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duminică, 5 august 2012

Critical Molecular Switch Discovered That Regulates Autophagy

The body has a built-in system known as autophagy, or 'self-eating,' that controls how cells live or die. Deregulation of autophagy is linked to the development of human diseases, including neural degeneration and cancer.

In a study published online this week in the Proceedings of the National Academy of Sciences, scientists at the Ludwig Institute for Cancer Research in Oxford discovered a critical molecular switch that regulates autophagy. They also studied the links between autophagy and a cellular process called senescence that stops cell growth permanently.

The researchers identified ASPP2, a tumor suppressor, as a molecular switch that can dictate the ability of a common cancer gene, known as the RAS oncogene, to either stop or promote senescence.

As Yihua Wang and researchers in Xin Lu's group at the Ludwig Institute investigated the life cycle of fibroblast cells - the most common connective tissue cells in animals - they found that reduced levels of the ASPP2 protein increase RAS oncogene-induced autophagic activity. This in turn prevented cells from entering senescence. Without ASPP2, the cells continued to proliferate unchecked, thereby promoting tumor growth.

ASPP2 is known to play a role in suppressing tumor development. Mice that have a deficiency or malfunction in this protein have a predisposition to developing tumors. And low ASPP2 levels in patients are linked to poor prognoses in cancers, such as large B-cell lymphomas. Reduced ASPP2 expression has also been observed in highly metastatic breast tumors. But until now, researchers did not understand why.

"We found that in the presence of the common cancer-causing RAS oncogene, ASPP2 interacted with a protein complex that is responsible for deciding cell fate via autophagy," said Yihua Wang, PhD, Ludwig researcher in Oxford.

"What this means is that the cell's emergency stop button is disabled when ASPP2 expression is reduced or lost, allowing it to proliferate unchecked as with cancer," added Wang.

"The balance between the RAS oncogene and ASPP2 activity is crucial to determining whether or not tumor growth is promoted. Our next step will be to identify ways to alter ASPP2 activity at that critical switch point. This could be an effective way to treat cancers with reduced ASPP2 expression and mutated RAS, such as breast and colon cancers," concluded Wang.

"Some of the recently developed anti-cancer drugs are potent inducers of autophagy. The new findings may also offer an explanation as to why patient response to these drugs can vary dramatically. There are factors at play within the body that can dictate authophagic activity and impact clinical outcomes," said Xin Lu, PhD, director of Ludwig's Oxford Branch. "While further study is needed, these findings may in the longer term help doctors to identify patients who are more likely to respond well to autophagic inhibition," added Lu.

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n.p. "Critical Molecular Switch Discovered That Regulates Autophagy." Medical News Today. MediLexicon, Intl., 3 Aug. 2012. Web.
5 Aug. 2012. APA

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'Critical Molecular Switch Discovered That Regulates Autophagy'

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joi, 15 decembrie 2011

Cancer Spread Can Be Predicted Through Molecular Markers

Main Category: Cancer / Oncology
Also Included In: Radiology / Nuclear Medicine; Lung Cancer
Article Date: 15 Dec 2011 - 0:00 PST

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Molecular markers found in cancer cells that have spread from a primary tumor to a limited number of distant sites can help physicians predict which patients with metastatic cancer will benefit from aggressive, targeted radiation therapy.

In a study published online in the journal PloS One, researchers from the University of Chicago show that if cells from metastatic tumors have high levels of a particular type of microRNA - a tool cells use to silence certain genes - not even aggressive treatment of those tumors would help. But if the cells have lower levels of that biological marker, then focused local treatment could be effective, even curative.

"We previously demonstrated that we could provide lasting disease-free survival to a percentage of patients with metastatic disease," said study author Ralph Weichselbaum, MD, professor and chair of radiation and cellular oncology and Director of the Ludwig Center for Metastasis Research at the University of Chicago. "This finding means we can have a pretty good sense in advance of which patients we can help. Patients unlikely to benefit from focused, local therapy can move on to systemic treatment."

When patients die from cancer, it is usually caused by distant metastases, numerous cancer sites established by malignant cells that split off from the primary cancer and began growing in new settings. In 1994, Weichselbaum and colleague Samuel Hellman proposed that there was a potentially curable intermediate state between cancer that had not spread at all and cancer that had spread extensively. They named this phenomenon "oligometastasis," meaning cancer that had spread to a few distant sites.

In 2004, they began a small clinical trial to test that theory. Patients with stage IV cancer with one to five distant metastases and no tumors bigger than 10 centimeters in diameter were enrolled. The results, published in 2008, showed that precisely targeted radiation therapy could eradicate all evidence of disease in about 20 percent of those patients.

"We were pleased to get such encouraging results in patients with stage IV cancers that had spread to distant sites," Weichselbaum said. "This was proof of principle in patients who had already failed standard therapies."

A follow-up study, published in October 2011, found that 18 percent of the patients in that initial trial had seen no progression of their cancers for the duration of the study and 27 percent developed no new tumor sites.

The next step was to determine in advance which patients were most likely to benefit from such targeted therapy and which ones should move on to whole-body treatments, such as chemotherapy. So they compared cells from secondary tumors from patients who did well in the original studies with those whose cancers went on to establish multiple metastatic sites.

They found that tumors that were highly proliferative, producing many metastases, had patterns of microRNA expression that differed from those that produced only a few. The tumors most likely to spread had high levels of a small nucleic acid known as microRNA-200c.

This came as a surprise. MicroRNA-200c was thought to suppress metastasis. But when the researchers boosted microRNA-200c levels in a mouse model of cancer, it significantly increased metastasis. The researchers subsequently showed that microRNA-200c reduced the activity of other genes that acted to prevent the spread of cancer.

Further tests in mouse models showed that boosting microRNA-200c levels significantly increased the metastatic potential of tumors that were not as prone to spread.

"Our findings are an initial step in discriminating between patients with a few treatable sites where the tumor has spread and those who will develop widespread metastasis, which is not curable with focused radiation therapy," Weichselbaum said. "It is encouraging to find a common molecular basis for this treatable state across a broad variety of metastases from solid tumors."

Oligometastases are "more common than generally recognized," the authors note. "Potentially, 50 percent of patients with metastatic non-small cell lung cancer, the leading cause of cancer death in men and women, may be oligometastatic."

When combined with other factors - the number and size of metastasis, the interval from treatment of a primary tumor to the appearance of metastasis, the microscopic structure and appearance of tumor tissue - the presence of microRNA-220c could become a key element of patient selection for targeted radiation therapy, Weichselbaum said, distinguishing between patients who have treatable tumors and those who have widespread metastasis, including many tumors too small to detect.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. The National Institutes of Health, the Ludwig Center for Metastasis Research, the University of Chicago Center for Radiation Therapy, the Chicago Tumor Institute, Dr. Lloyd Old, Mr. And Mrs. Vincent Foglia and the Foglia Family Foundation, the Lung Cancer Research Foundation, the University of Chicago Cancer Research Foundation, the University of Chicago Comprehensive Cancer Center and the Center for the Multiscale Analysis of Genomic and Cellular Networks supported this study. Additional authors include Yves Lussier of the University of Illinois at Chicago; Rosie Xing, Nikolai Khodarevi, Yong Huang, Qingbei Zhang, Sajid Khan, Xinan Yang, Michael Hasselle, Thomas Darga, Renuka Malik, Hanli Fan, Samantha Perakis, Matthew Filippo, Kimberly Corbin, Younghee Lee, Mitchell C. Posner, Steven J. Chmura, and Samuel Hellman of the University of Chicago Medical Center, and Joseph Salama of Duke University Medical Center.
University of Chicago Medical Center Please use one of the following formats to cite this article in your essay, paper or report:

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joi, 8 decembrie 2011

In Early Vs. Late Hormone Receptor-Positive Breast Cancer, Molecular Differences May Be Used To Predict Breast Cancer Recurrence

Main Category: Breast Cancer
Also Included In: Genetics
Article Date: 08 Dec 2011 - 0:00 PST

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Researchers may have discovered a series of genes that will help predict whether or not a woman with hormone receptor-positive invasive breast cancer will experience early, late or no recurrence of her disease.

Minetta C. Liu, M.D., associate professor of medicine and oncology and director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 6-10, 2011.

"There are clear biological differences within the supposedly unified group of hormone receptor (HR)-positive breast cancers, and these differences distinguish subtypes relative to the time at which they recur," Liu said. "Understanding what drives these distinctions will allow us to tailor treatment and improve patient outcomes."

Women with HR-positive breast cancer are frequently treated with tamoxifen, which is credited with saving the lives of hundreds of thousands of women. Although tamoxifen prevents or delays cancer recurrence in many women, some will recur 10 years or more from their original diagnosis. Until now, the molecular basis for this recurrence pattern was unknown.

Liu and colleagues, in collaboration with investigators from the University of Edinburgh, evaluated high-quality frozen tumor samples obtained at the time of breast cancer diagnosis. These tissue samples were linked to data on treatment and clinical outcomes, allowing researchers to analyze gene expression patterns present before the initiation of any systemic therapy.

Together with engineers at Virginia Polytechnic Institute, Liu and colleagues identified significant gene expression patterns among the tumor samples. These patterns correlated strongly with the development of distant metastatic disease.

"We confirmed what many have already suspected," said Liu. "There are biological drivers that define - at the time of tumor development - whether or not breast cancer will recur early, late or not at all. Now we need to validate these findings and take our knowledge to the next step."

Liu hopes that this research can be used to help personalize treatment in day-to-day clinical practice. "Endocrine therapy and chemotherapy are not without toxicity," she said. "The ability to predict which patients will recur early in their treatment course can lead to more appropriate recommendations for adjuvant chemotherapy. It might also identify those women who would benefit most from studies using investigational agents to enhance the effects of tamoxifen or aromatase inhibitors."

She added: "At the other extreme are those patients with HR-positive tumors who recur long after completing five years of endocrine therapy. These are the patients for whom extended endocrine therapy and its related side effects are really worth it."

The team's next step is to validate their predictive model for the timing of recurrences on tamoxifen so that physicians and patients can make more informed decisions about the potential added benefits of adjuvant chemotherapy, extended endocrine therapy and involvement in clinical trials. They will also investigate combinations of molecular targets with the ultimate goal of delaying or preventing the development of metastatic breast cancer, Liu said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our breast cancer section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

MLA

American Association for Cancer Research. "In Early Vs. Late Hormone Receptor-Positive Breast Cancer, Molecular Differences May Be Used To Predict Breast Cancer Recurrence." Medical News Today. MediLexicon, Intl., 8 Dec. 2011. Web.
8 Dec. 2011. APA
American Association for Cancer Research. (2011, December 8). "In Early Vs. Late Hormone Receptor-Positive Breast Cancer, Molecular Differences May Be Used To Predict Breast Cancer Recurrence." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/238755.php.

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