Posts Tagged ‘breast’

Circulating tumor cell clusters more likely to cause metastasis than single cells

“While CTCs are considered to be precursors of metastasis, the significance of CTC clusters, which are readily detected using devices developed here at MGH, has remained elusive,” says Shyamala Maheswaran, PhD, of the MGH Cancer Center, co-senior author of the Cell paper. “Our findings that the presence of CTC clusters in the blood of cancer patients is associated with poor prognosis may identify a novel and potentially targetable step in the blood-borne spread of cancer.”

In their experiments the team used two versions of a microfluidic device called the CTC-Chip — both developed at the MGH Center for Engineering in Medicine — that captures CTCs from blood samples in ways that make the cells accessible for scientific testing. One version — the HBCTC-Chip — can efficiently capture extremely rare CTCs in a blood sample. Another version, the CTC-iChip, rapidly isolates CTCs in a way that does not rely on preidentified tumor antigens, allowing capture of cells with gene expression patterns that may be missed by the antibodies used in the HBCTC-Chip.

A series of experiments in animal models of breast cancer revealed that:

  • CTC clusters are made up of cells that probably were adjacent to each other in the primary tumor, not cells that proliferated after entering the bloodstream.
  • Although CTC clusters make up only 2 to 5 percent of all CTCs, they contributed to around half of lung metastases resulting from implanted breast tumors, indicating a metastatic potential 23 to 50 times greater than single CTCs.
  • CTC clusters injected into mice survived in greater numbers than did single CTCs, and metastases developing from clusters led to significantly reduced survival.
  • CTC clusters disappear from the animals’ bloodstreams more rapidly than do single CTCs, probably because they become lodged in capillaries where they give rise to metastases.

Analysis of blood samples taken at several points in time from a group of patients with different forms of advanced metastatic breast cancer found CTC clusters in the blood of 35 percent of patients and that the survival of those with more clusters in their blood was significantly reduced. Similar analysis of samples from a group of prostate cancer patients also found an association between the presence of CTC clusters and dramatically reduced survival.

RNA sequencing of both single and clustered CTCs from breast cancer patients identified several genes expressed at elevated levels in CTC clusters, one of which — a protein called plakoglobin — also was overexpressed in the primary tumors of patients with reduced survival. Analysis of blood and tissue samples from one patient revealed that plakoglobin was expressed in CTC clusters but not single CTCs and also was expressed in some portions of both the primary tumor and metastases. Plakoglobin is a component of two important structures involved in cell-to-cell adhesion, and the investigators found that suppressing its expression caused CTC clusters to fall apart, reducing their metastatic potential, and also disrupted cell-to-cell contact between breast cancer cells but not normal breast tissue.

“It is possible that therapeutically targeting plakoglobin or pathways involved in cell-to-cell adhesion within cancer cells could be clinically useful, especially in patients in whom CTC clusters are found,” says Nicola Aceto, PhD, of the MGH Cancer Center and lead author of the Cell paper. “We need to investigate that possibility along with determining whether further characterization of both single CTCs and CTC clusters will provide further insight into differences in their biology, drug responsiveness and their contribution to the process of metastasis.”

source : http://www.sciencedaily.com/releases/2014/08/140828135519.htm

Some women still don’t underststand ‘overdiagnosis’ risk in breast screening

In a survey of around 2,200 women, Cancer Research UK scientists at University College London (UCL) found that 64 per cent felt they fully understood the information given about overdiagnosis — the chance that screening will pick up cancers that would never have gone on to cause any harm — by the National breast screening programme.

Information about overdiagnosis has only been included in the NHS breast screening invitation leaflets since late 2013, meaning that overdiagnosis is likely to be a new concept for many people.

But despite uncertainty over the information they were given, intentions to attend breast screening remained high, with only seven per cent of women saying they would be less likely to attend screening after receiving the overdiagnosis information. On the other hand, four per cent of women said they would be more likely to attend screening after receiving the information.

Study author, Dr Jo Waller, a researcher at the Health Behaviour Research Centre at UCL, said: “While there is clearly room for improvement, the information leaflet does appear to help some women make a decision about whether or not to have breast screening.

“But the study found that many women still struggle to understand the balance of benefits and harms linked to breast screening, so we need to find better ways to communicate the risks as well as the benefits.”

Overdiagnosis happens because some breast cancers grow so slowly that it would take more than a lifetime for them to threaten a woman’s health. For every life that is saved through screening, researchers estimate that around three women will be overdiagnosed with breast cancer, although there is presently no way of telling the difference between life-threatening cancers and cancers that are overdiagnosed, either at diagnosis or after treatment.

Sara Hiom, Cancer Research UK’s director of early diagnosis, said: “We think it’s vitally important for women to have clear information about breast screening, the balance of benefits and harms and the fact that they could be diagnosed with and treated for a cancer that might not have caused them harm.

“We are committed to providing quality information that can help women understand the harms and benefits of breast screening, and research like this can help us refine the information we offer to be sure that it is as helpful and understandable as possible.

“The concept of overdiagnosis is still very new for a lot of women because it has only been included in the NHS leaflets for a year. We hope that over time, people’s understanding of this concept will increase as more and more women receive information explaining this risk of screening.

“Any woman invited for breast screening and worried about the risks of overdiagnosis can speak to our specialist cancer nurses on freephone 0808 800 4040.”

source : http://www.sciencedaily.com/releases/2014/08/140829083906.htm

New estrogen-based compound suppresses binge-like eating behavior in female mice

“Previous data has shown that women who have irregular menstrual cycles tend to be more likely to binge eat, suggesting that hormones in women play a significant role in the development or prevention of the behavior,” said Dr. Yong Xu, assistant professor of pediatrics and senior author of the paper. “Previous data has also shown that in humans, there is a strong association between estrogen and binge eating. When estrogen is high, binge eating is inhibited, but when estrogen is low, binge eating becomes more frequent. Using mouse models, we set out to see what the effects of estrogen were on binge behavior in female mice.”

In this study, Xu and colleagues first found that estrogen can strongly inhibit binge eating in mice, which was consistent with data in humans.

“We can speculate that in women who develop binge eating who also happen to have irregular menstrual cycles, it is probably because their estrogen function is somehow damaged, which is what leads to the development of binge eating,” said Xu.

Xu and colleagues went further to determine what receptor was mediating the estrogen effect on binge eating and where this receptor was located. Using genetic mouse models, they found that the estrogen receptor-α, expressed by serotonin neurons in the brain, mediates the effect of estrogen to suppress binge eating.

“The significance is not only understanding the mechanism of how estrogen may modulate this behavior, but from a more therapeutic point of view, this would identify a potential target for estrogen therapy or modified estrogen therapy for treatment of this problem,” said Xu.

However, Xu notes that the current estrogen therapy in practice has been a problem because it produces detrimental effects, such as high risk of breast cancer.

“We thought, if we can understand where and how the estrogen acts to produce some benefits, maybe that will facilitate the development of an estrogen-based therapy that could be more specific and would just produce the benefits and bypass the side effects, such as breast cancer,” he said.

Around this same time, Xu’s collaborators at Indiana University developed a compound called GLP-1-estrogen, which was a conjugate between the peptide GLP-1 and estrogen. The idea was that GLP-1 would be used to carry the estrogen and deliver it to a region where there are GLP-1 receptors as well as estrogen receptors and the estrogen would be released there, producing a biological function. His collaborators at Indiana University published that this compound was good for body weight control and would not increase the risk of breast cancer because the compound did not deliver estrogen to the breast tissue.

Xu and colleagues used this compound to show that when a systemic injection of this compound is given in mice, there is increased activity of estrogen in the serotonin region of the brain, meaning the compound can deliver estrogen in the serotonin region where they believed binge behavior is regulated.

They further showed that the compound actually substantially inhibits binge eating in mice, and their data showed that part of this effect comes from the estrogen and the other part of the effect comes from the GLP-1.

“There are a few studies showing that binge patients tend to have decreased GLP-1 in their blood, but nobody had shown that GLP-1 suppresses binge eating in animals or humans until now,” said Xu. “We showed that these two things, estrogen and GLP-1, work together to decrease binge eating and that GLP-1 can carry estrogen to this specific site to produce a benefit, but bypasses the breast tissue.”

Xu notes that this provides a strong case for an interventional drug that specifically acts on estrogen receptor-α in the serotonin region of the brain to treat binge eating.

The next steps in Xu’s research will be to determine the mechanism by which estrogen regulates serotonin neurons. He and colleagues also hope to go downstream of serotonin to see if increasing serotonin release inhibits binge eating.

source : http://www.sciencedaily.com/releases/2014/08/140826205515.htm