Posts Tagged ‘receptor’

Carcinogenic role of protein in liver decoded

The EGF Receptor (Epidermal Growth Factor Receptor, EGFR) is a protein which, as a transmembrane receptor, controls a multitude of vital processes in the cell. In human beings, the EGF Receptor is present in many cells types and plays an important role in many types of cancer. It is present in various kinds of tumors in excessive amounts and/or in mutated form, which causes the tumor cells to grow and multiply. For this reason the EGFR serves as a point of attack in many treatment strategies. In the process, its function is inhibited with the objective of slowing down the growth of the tumor cell.

The liver cell carcinoma (hepatocellular carcinoma, short HCC) is one of the most frequent malignant tumors worldwide. Approximately six percent of all cancers in men and about three percent in women are liver cell carcinomas. It is the second most frequent cause of death associated with cancer. Risk factors for HCC include liver diseases through Hepatitis B and C infections as well as alcohol abuse or the classic “fatty liver.”

Up to now, the tumor-promoting role of EGFR has only been linked with its expression directly in the tumor cells. However, the study group of Maria Sibilia, Manager of the Institute for Cancer Research at the Medical University of Vienna and Deputy Manager of the Comprehensive Cancer Centre, in cooperation with the research groups of Michael Trauner and Markus Peck-Radosavljevic at the clinical division for gastroenterology and hepatology (Manager: Michael Trauner) as well as the Eastern Hepatobiliary Surgery Institute/Hospital in Shanghai discovered that EGFR plays a more decisive role in the macrophages of the liver (these are important cells of the immune system which are called Kupffer cells in the liver) with respect to the growth of the liver cell carcinoma than previously assumed.

“In this study we were able to prove that the inhibition of EGFR has a tumor inhibiting effect on the macrophages and not its inhibition on the tumor cell itself,” explains Maria Sibilia. However, if the EGFR conversely exists on these macrophages in an excessive number, it can promote the growth of the tumor. Its existence on the macrophages reduces the chance of survival for HCC patients.

This could explain why EGFR inhibitors utilised for cancer treatment and aiming directly for the tumor cells have achieved clinically disappointing results in the fight against the liver cell carcinoma in the past. For the first time, this study proves the tumor-promoting mechanism for EGFR in non-tumor cells, which could lead to more effective and precise treatment strategies with macrophages as a point of approach in the future.

source : http://www.sciencedaily.com/releases/2014/09/140901090303.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

Finding keys to glioblastoma therapeutic resistance

“There is a growing interest to guide cancer therapy by sequencing the DNA of the cancer cell,” said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, UC San Diego Division of Neurosurgery and the principal investigator of the study. “Our study demonstrates that the sensitivity of glioblastoma to a drug is influenced not only by the content of its DNA sequences, but also by how the DNA sequences are organized and interpreted by the cell.”

The team of scientists, led by Chen, used a method called comparative gene signature analysis to study the genetic profiles of tumor specimens collected from approximately 900 glioblastoma patients. The method allows investigators to discriminate whether specific cellular processes are “turned on” or “turned off” in glioblastomas. “Our study showed that not all glioblastomas are the same. We were able to classify glioblastomas based on the type of cellular processes that the cancer cells used to drive tumor growth,” said Jie Li, PhD, senior postdoctoral researcher in the Center for Theoretical and Applied Neuro-Oncology at UC San Diego and co-first author of the paper.

One of these cellular processes involves Epidermal Growth Factor Receptor (EGFR). The study revealed that EGFR signaling is suppressed in a subset of glioblastomas. Importantly, this suppression is not the result of altered DNA sequences or mutations. Instead, EGFR is turned off as a result of how the DNA encoding the EGFR gene is organized in the cancer cell. This form of regulation is termed “epigenetic.” Because EGFR is turned off in these glioblastomas, they become insensitive to drugs designed to inhibit EGFR signaling.

“Our research suggests that the selection of appropriate therapies for our brain tumor patients will require a meaningful synthesis of genetic and epigenetic information derived from the cancer cell,” said co-first author Zachary J. Taich.

The paper’s abstract can be found at: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2350

source : http://www.sciencedaily.com/releases/2014/08/140825185321.htm