Tumour "Tweets" Influence Other Cells

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Tumour "Tweets" Influence Other Cells

Groundbreaking research from Australia reveals that brain tumours release small bits of information, rather like "tweets", that interact with blood vessel cells in a way that causes them to undergo significant changes. The researchers believe the discovery may lead to new treatments.

Writing in the 17 June online issue of RNA Biology, Michael Buckland, associate professor in the University of Sydney's Brain and Mind Research Institute (BMRI), and colleagues, describe how they found brain tumours release microvesicles containing new forms of RNA, and these interact with nearby brain blood vessel cells.

RNA (short for ribonucleic acid), a close cousin of DNA, is a group of long-chained molecules that among other things, control gene expression and help transfer the genetic code held in DNA to make proteins.

Microvesicles are tiny pockets of cell plasma, enclosed in a membrane. They are released by cells and were once considered to be junk, or debris.

Buckland says scientists are just becoming aware of the significance of microvesicles, and how they may be important for health and disease.

For instance, there have been suggestions that microvesicles may have potential as clinical biomarkers for individual cancers.

"It seems that many cells release microvesicles allowing them to communicate and influence other cells nearby and in distant parts of the body in real-time - much like tweeting," Buckland says in a statement.

Tumours thrive in different environments to healthy tissue. As the tumour grows it interacts with its environment, for instance changing the blood supply to suit its own needs.

To do this the tumour must interact with other cells, and modify their gene expression so they make the proteins that suit the tumour rather than those that suit healthy tissue.

The team had a hunch that one way brain tumour cells (gliomas) do this is via the microvesicles.

So they designed a study that took an "unbiased approach to identifying RNAs in glioma-derived microvesicles, and explored their potential to regulate gene expression in recipient cells".

For the study, the team grew brain tumour cells (gliomas) in culture and harvested the microvesicles they released into the culture medium.

When they added the glioma-produced microvesicles to cultures of brain blood vessel cells, they triggered significant changes in the cells, including many changes in gene expression.

On closer examination they found that the glioma microvesicles contained complex populations of coding and non-coding RNA, and the proportions of these populations were different to those from the cells they came from.

Compared to the glioma cells that made them, glioma microvesicles had lower levels of microRNA and higher levels of unusual or new non-coding RNA, most of which "have no known function", write the authors, who conclude:

"Our data suggest that the scope of potential actions of tumor-derived microvesicles is much broader and more complex than previously supposed, and highlight a number of new classes of small RNA that remain to be characterized."

Buckland says their findings suggest microvesicles "likely to play an important role in the changes to blood vessels seen in high grade brain tumours, the most common form in Australian adults".

They present a new target for treatment against brain tumours, he says, adding that:

"Furthermore, they can be detected in the blood of patients with brain tumours, and may be an important diagnostic tool in the future."

A biosciences company has also suggested, at a scientific meeting in 2011, that the fact circulating microvesicles have different RNA profiles highlights their potential use in cancer detection and monitoring.

Written by Catharine Paddock PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our biology / biochemistry section for the latest news on this subject. "Glioma microvesicles carry selectively packaged coding and noncoding RNAs which alter gene expression in recipient cells"; Cheryl C.Y. Li, Sally Eaton, Paul E. Young, Maggie Lee, Rupert Shuttleworth, David T. Humphreys, Georges E. Grau, Valery Combes, Mary Bebawy, Joyce Gong, Susan Brammah, Michael E. Buckland, and Catherine M. Suter; RNA Biology, Volume 10, Issue 8, published online 17 June 2013; Link to Abstract.
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Genetic Differences May Influence the Severity of Joint Pain Among Breast Cancer Patients Taking Aromatase Inhibitors

Aromatase inhibitor-associated arthralgia (AIAA)? is a major side effect in breast cancer survivors, producing joint pain so severe that as many as ten percent of women discontinue their therapy prematurely while undergoing treatment with these lifesaving drugs. New research presented by investigators from the University of Pennsylvania’s Abramson Cancer Center at the 2010 meeting of the American Society of Clinical Oncology reveals a possible genetic basis for why these side effects occur and shows promise for treating these symptoms without interfering with the drugs’ efficacy. Additional research will also be presented shedding light on the physical and psychological factors that influence women’s decisions to stop taking the drugs.

Jun Mao, MD, MSCE, an assistant professor of Family Medicine and Community Health who heads the Abramson Cancer Center’s integrative oncology program, led a team that studied individual genetic variations that could potentially influence both the onset and the severity of AIAA.[1] His team studied 390 postmenopausal women with Stage 0 to III breast cancer receiving adjuvant therapy with aromatase inhibitors who reported joint pain related to their drug therapy.? They found that among this group, women carrying at least one copy of a “7-repeat” genetic variant in the aromatase enzyme (CYP19A1, the target of aromatase inhibitors) had a lower chance of developing AAIA than those with at least one “8-repeat” allele of the same gene. Having at least one copy of a specific IL-6 haplotype was also correlated with increased pain severity, while the presence of a different variant of that gene was associated with decreased pain.? Both these findings support previous research that indicates an important role for host estrogen metabolism and inflammation in causing AIAA.

“Due to genetic differences, women respond differently to aromatase inhibitors with regard to estrogen levels and inflammatory processes, and as a result, some women are more likely to have this pain or have more severe pain,” says Angela DeMichele, MD, MSCE, an associate professor of Hematology/Oncology and Epidemiology and Biostatistics, and a co-author on all three of the studies. “There are millions of women receiving AIs, as many as 50 percent of them experience some level of arthralgia, and up to 10 percent discontinue their treatment prematurely, so this is a significant issue.”

The investigators say that as more breast cancer patients become breast cancer survivors, clinicians must become more knowledgeable about the quality of life issues impacting women after they end active treatment for their cancers. The new findings are key to identifying which women may be at risk of problems like arthralgia—and then, Mao says, to developing more targeted interventions at both the physical and psychological levels.

The multidisciplinary team is also looking at issues related to clinician-patient communication, exercise, and co-factors such as arthritis or fibromyalgia that can increase pain and disability in order to keep more women on their treatment regimen. Mao, who is also a licensed physician acupuncturist, has begun a clinical trial examining the effectiveness of acupuncture for aromatase inhibitor associated arthralgia as part of conventional breast cancer survivorship care. These efforts are part of the Abramson Cancer Center’s comprehensive Wellness After Breast Cancer program.

“We believe that proactively informing women about the possibility that their breast cancer treatment may cause arthralgia and then intervening early is probably important to keeping them on these potentially life-saving cancer treatments,” Mao says. “When they are not prepared, or become frustrated because they didn’t know this could happen to them, they are far more likely to make the decision to stop treatment. Some studies have suggested that women with the most severe symptoms are those with the most complete blockage of aromatase. We want to do everything we can to assure that the women most likely to benefit from therapy don’t end it too soon because they are experiencing pain related to their treatment.”

In a related study, University of Pennsylvania researchers surveyed 300 breast cancer survivors to assess the impact of AIAA on upper and lower extremity functioning.[2] They found that women with AIAA had greater impairment of both upper and lower extremities than those who did not experience these symptoms. As many as 29 percent of participants reported that the pain limited their ability to perform their normal activities.

In a third study, Carrie Stricker, PhD, RN, clinical assistant professor of Nursing and an oncology nurse practitioner, led the team of researchers in surveying 490 postmenopausal, non-metastatic breast cancer patients to assess the factors that influenced their stopping AI therapy prematurely.[3]? This is one of only a few studies to analyze the rates at which women discontinue AI therapy and the variables that predict their decision to do so, and the only designed to evaluate patient-reported reasons for ending AI treatment. The study found that 7 percent of the patients studied had discontinued their AI treatment early, at a mean of 15.7 months from the beginning of treatment. The most significant predictors for stopping therapy were a previous history of taking tamoxifen, which can also cause arthralgia and other symptoms; having other inflammatory conditions such as arthritis; communication about difficulties with taking AIs, and being married. Patients who stopped AI treatment early cited side effects as the main reason, with arthralgia being the most common complaint. Effects on bone, hot flashes, and cognitive effects were also named as reasons for cessation of therapy.

“These data suggest that we can develop a profile of the women who are most likely to make the decision to terminate their AI therapy prematurely, and if we can do that, we can design better supportive interventions for these women and incorporate them into our clinical practice,” DeMichele says. “This information, derived directly from the patients themselves, reinforces our understanding that assessing and managing the side effects of cancer therapy, including joint pain, is critical to the overall success we can achieve in managing the disease itself.”

References:

[1] Mao J, Su I, Feng R et al. Genetic variation in CYP19A1 and interleukin-6 and aromatase inhibitor-associated arthralgia in breast cancer survivors. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 526.

[2] Stricker CT, Palmer SC, DeMichele A, Mao J. Understanding premature discontinuation of aromatase inhibitor (AI) therapy in postmenopausal breast cancer survivors. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 6073.

[3] Friedman CF, Bruner D, Xie S et al. Functional disability and aromatase inhibitor-associated arthralgia in breast cancer survivors. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 9156.

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