Research points to potential new treatment for hard-to-treat cancers
Researchers at Huntsman Cancer Institute (HCI) at the University of Utah have found that defects in how cells are squeezed out of overcrowded tissue to die, a process called extrusion, may be a mechanism by which pancreatic cancer begins. From these findings, they may have identified an effective way to reverse the defective extrusion's effects without destroying normal tissues nearby. The results were published in the latest edition of the journal eLife.
The study focuses on the epithelia, tissues lining the cavities and surfaces of structures throughout the body, including organs such as the pancreas. It is already well-established that most solid tumors arise from this type of tissue.
The team analyzed previous published microarray data and found that a receptor for the lipid sphingosine 1-phosphate (S1P2) that is critical for the extrusion process, is significantly reduced in the most common type of pancreas cancer known as pancreatic ductal adenocarcinoma (PDAC), lung cancer, and some types of colon cancer--all aggressive cancers that resist treatment with chemotherapy.
Focusing on cells from PDAC tumors, the team found that reduced S1P2 levels led to reduced extrusion and cell death rates. About 50% of the cells did not extrude and formed masses, while most of the remaining ones extruded underneath instead of outside the cell layer.
"This kind of altered extrusion may be a common hallmark of invasive tumor types," said Jody Rosenblatt, PhD, co-author of the study, associate professor in the Department of Oncological Sciences at the University of Utah School of Medicine, and an HCI investigator. "While the mechanisms that drive tumor cell invasion are not yet clear, the results suggest that S1P2-mediated extrusion may play an important role in metastatic cell invasion."
Normally, signaling through S1P2 triggers epithelial cells to squeeze some cells out to die when overcrowding occurs in order to keep constant healthy numbers. "Usually, cells pop out, away from underlying tissue," said Rosenblatt. "Looking at zebrafish, we found that when the S1P2 signal is disrupted, cells build up and form masses that resist cell death--even when it is triggered by chemotherapy--or they pop into underlying tissue where they can potentially invade. Also, some cells die without being extruded, creating poor barrier function in the epithelium, which could cause chronic inflammation."
According to Rosenblatt, decades of previous research has established all these conditions--masses of cells, resistance to cell death, invasive activity, and chronic inflammation--as determining factors of cells becoming tumors and progressing into metastasis.
Normally, extruded cells ultimately die because survival signaling, which depends on a signal called focal adhesion kinase (FAK), is lost. The team tested whether defective extrusion could be bypassed by using inhibitors to FAK. Simply adding FAK inhibitors rescued cell death rates to normal, and surprisingly, eliminated the large cell masses and improved the barrier function.
"Some FAK inhibitors are already being tested in clinical trials for other types of cancers," said Rosenblatt. "Hopefully, they may also be a better therapy for recalcitrant tumors such as pancreas cancers and some lung cancers.
"Our results so far have focused on the primary tumor or cells invading in culture. Now we need to see if we can target cells that have moved to other sites, or metastasized, with FAK inhibitors, since this is an important feature of pancreatic cancer. That's the next phase of our study," said Rosenblatt.
Watch a video about the research: https:/
Yapeng Gu, PhD; Gloria Slattum, PhD; members of HCI's Rosenblatt lab, are co-authors of this article. Other co-authors include Jill Shea, PhD; Matthew Firpo, PhD; and Sean Mulvihill, MD, and Margaret Alexander from the University of Utah, and Vita Golubovskaya, PhD, of Roswell Park Cancer Institute in Buffalo, New York.
This study was supported by a National Institute of Health Director's New Innovator Award 1DP2OD002056-01, as well as R01GM102169 and P30CA042014. The University of Utah provided a Funding Incentive Seed Grant and Huntsman Cancer Foundation also provided research support funding.
About Huntsman Cancer Institute at the University of Utah
Huntsman Cancer Institute (HCI) is one of the world's top academic research and cancer treatment centers. HCI manages the Utah Population Database - the largest genetic database in the world, with more than 16 million records linked to genealogies, health records, and vital statistics. Using this data, HCI researchers have identified cancer-causing genes, including the genes responsible for melanoma, colon and breast cancer, and paraganglioma. HCI is a member of the National Comprehensive Cancer Network (a 23-member alliance of the world's leading cancer centers) and is a National Cancer Institute-Designated Cancer Center. HCI treats patients with all forms of cancer and operates several high-risk clinics that focus on melanoma and breast, colon, and pancreas cancers. The HCI Cancer Learning Center for patient and public education contains one of the nation's largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, Sr., a Utah philanthropist, industrialist, and cancer survivor.
Linda Aagard | EurekAlert!
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
CWRU researchers find a chemical solution to shrink digital data storage
22.06.2017 | Case Western Reserve University
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
Germany counts high-precision manufacturing processes among its advantages as a location. It’s not just the aerospace and automotive industries that require almost waste-free, high-precision manufacturing to provide an efficient way of testing the shape and orientation tolerances of products. Since current inline measurement technology not yet provides the required accuracy, the Fraunhofer Institute for Laser Technology ILT is collaborating with four renowned industry partners in the INSPIRE project to develop inline sensors with a new accuracy class. Funded by the German Federal Ministry of Education and Research (BMBF), the project is scheduled to run until the end of 2019.
New Manufacturing Technologies for New Products
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
22.06.2017 | Life Sciences
22.06.2017 | Materials Sciences
22.06.2017 | Materials Sciences