Archive for the ‘Gastroenterology’ Category

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

Drug shows promise for subset of stage III colon cancer patients

When added to the standard chemotherapy treatment — fluorouracil and leucovorin — adjuvant irinotecan therapy improved overall survival rates for patients with the CpG island methylator phenotype (CIMP). CIMP is seen in about 10 to 20 percent of colorectal cancers. Patients with CIMP-negative tumors, however, exhibited significant harm from the addition of irinotecan — overall survival was 68 percent compared with 78 percent for those receiving the standard treatment alone.

“Our results serve as an example that the molecular characterization of individual tumors may help to determine the most appropriate treatment for patients with colon cancer,” said lead study author Stacey Shiovitz, MD, from the department of medicine, University of Washington, Seattle, WA, and the clinical research division of Fred Hutchinson Cancer Research Center, also in Seattle. “Based on our findings, identification of a tumor’s CIMP status should play a greater role in the clinical setting.”

Researchers analyzed data from patients with stage III colon cancer randomly assigned to groups given fluorouracil and leucovorin or adjuvant irinotecan after surgery, from April 1999 through April 2001. Patients were followed for eight years. Patients with CIMP-positive tumors demonstrated a trend toward improved overall survival when treated with irinotecan versus the standard treatment alone, 69 percent versus 56 percent, respectively. Results were most pronounced among patients with stage III CIMP-positive, mismatch repair intact (MMR-I) colon cancer.

No significant associations or interactions between CIMP and KRAS or BRAF mutations were observed, suggesting that the effectiveness of this treatment is not influenced by KRAS/BRAF mutation status.

“This analysis serves to increase our understanding of which subset of patients might benefit from irinotecan adjuvant therapy. This research is an important step in the medical community’s work to classify tumors into groups that would result in optimized treatment strategies, thus delivering a higher level of personalized care to patients,” added Dr. Shiovitz.

Future studies are needed to better understand the origin of the CIMP phenotype and to test these findings in a larger subset.

source : http://www.sciencedaily.com/releases/2014/08/140828110824.htm

Growing human GI cells may lead to personalized treatments

Reporting online recently in the journal Gut, researchers at Washington University School of Medicine in St. Louis said they have made cell lines from individual patients in as little as two weeks. They have created more than 65 such cell lines using tissue from 47 patients who had routine endoscopic screening procedures, such as colonoscopies. A cell line is a population of cells in culture with the same genetic makeup.

The scientists said the cell lines can help them understand the underlying problems in the GI tracts of individual patients and be used to test new treatments.

“While it has been technically possible to isolate intestinal epithelial stem cells from patients, it has been challenging to use the material in ways that would benefit them on an individual basis,” said co-senior investigator Thaddeus S. Stappenbeck, MD, PhD, a professor of pathology and immunology. “This study advances the field in that we have developed new methods that allow for the rapid expansion of intestinal epithelial stem cells in culture. That breaks a bottleneck and allows us to develop new ways to test drug and environmental interactions in specific patients.”

To grow the human cells, the researchers adapted a system used to grow intestinal epithelial stem cells in mice. In the GI tract, epithelial cells line the inner surface of the esophagus, stomach and intestines.

“An additional important feature of this system is that we can isolate stem cell lines from intestinal biopsies,” said first author Kelli L. VanDussen, PhD, a postdoctoral fellow in Stappenbeck’s laboratory. “These biopsies are very small tissue fragments that are routinely collected by a gastroenterologist during endoscopy procedures. We have refined this technique, so we have nearly 100 percent success in creating cell lines from individual patient biopsies.”

The researchers developed an experimental system that created high levels of critical factors to isolate and expand intestinal epithelial stem cells, including a signaling protein called Wnt and a related protein called R-spondin, which enhances the Wnt signal. They also exposed the cells to a protein called Noggin, which prevented the cells from differentiating into other cell types that live in the GI tract.

After growing the intestinal cell lines, the investigators collaborated with Phillip I. Tarr, MD, the Melvin E. Carnahan Professor of Pediatrics and director of the Division of Pediatric Gastroenterology and Nutrition, to conduct experiments and see how the cells interacted with bacterial pathogens like E. coli.

This showed that pathogenic strains of E. coli attached to intestinal epithelial cells. That attachment is thought to be the critical step in stimulating disease. The investigators said the experimental system they created should lead to new methods to uncover therapies for treating bacterial infections of the intestine.

“In the past, the only really robust method for studying GI epithelial cells was to use cancer cell lines,” said co-senior investigator Matthew A. Ciorba, MD, a gastroenterologist and assistant professor of medicine. “However, cancer cells behave differently than the noncancerous GI epithelium, which is affected in patients with conditions such as inflammatory bowel disease. This technique now allows us to study cells identical to the ones that live in a patient’s GI tract. Plus, we can grow the cell lines quickly enough that it should be possible to develop a personalized approach to understanding a patient’s disease and to tailor treatment based on a patient’s underlying problem.”

The researchers said the new technique is relatively simple and inexpensive and could easily be adapted for use in other laboratories.

“You can grow these cells, differentiate them and then test various therapies using these cells,” Stappenbeck explained. “If we want to learn whether particular patients have a susceptibility to certain types of infections, we can test that. We’re very excited about this going forward because we’re entering new territory. We’ve never been able to do this before.”

Looking ahead, the researchers believe these cell lines will be useful in testing for new drug targets, for vaccine development and to better understand how these human cells interact with the beneficial and the harmful microbes that also live in the gut.

source : http://www.sciencedaily.com/releases/2014/08/140807121850.htm