Posts Tagged ‘researchers’

Enzyme controlling metastasis of breast cancer identified

“The take-home message of the study is that we have found a way to target breast cancer metastasis through a pathway regulated by an enzyme,” said lead author Xuefeng Wu, PhD, a postdoctoral researcher at UC San Diego.

The enzyme, called UBC13, was found to be present in breast cancer cells at two to three times the levels of normal healthy cells. Although the enzyme’s role in regulating normal cell growth and healthy immune system function is well-documented, the study is among the first to show a link to the spread of breast cancer.

Specifically, Wu and colleagues with the UC San Diego Moores Cancer Center found that the enzyme regulates cancer cells’ ability to transmit signals that stimulate cell growth and survival by regulating the activity of a protein called p38 which when “knocked down” prevents metastasis. Of clinical note, the researchers said a compound that inhibits the activation of p38 is already being tested for treatment of rheumatoid arthritis.

In their experiments, scientists took human breast cancer cell lines and used a lentivirus to silence the expression of both the UBC13 and p38 proteins. These altered cancer cells were then injected into the mammary tissues of mice. Although the primary tumors grew in these mice, their cancers did not spread.

“Primary tumors are not normally lethal,” Wu said. “The real danger is cancer cells that have successfully left the primary site, escaped through the blood vessels and invaded new organs. It may be only a few cells that escape, but they are aggressive. Our study shows we may be able to block these cells and save lives.”

Researchers have also defined a metastasis gene signature that can be used to evaluate clinical responses to cancer therapies that target the metastasis pathway.

source : http://www.sciencedaily.com/releases/2014/09/140902205145.htm

Natural killer cells battle pediatric leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. This disease hinders the development of healthy blood cells while cancer cells proliferate. Currently, children with ALL receive chemotherapy for two to three years, exposing them to significant side effects including changes in normal development and future fertility.

As a way to avoid these adverse effects, investigators have been researching how to supercharge the body’s innate cancer-fighting ability — a technique called immunotherapy. One branch of the immune system — and a possible component of immunotherapy — includes a class of cells called natural killer (NK) cells. These specialized white blood cells police the body and destroy abnormal cells before they turn cancerous.

Using NK cells as immunotherapy presents challenges. If the cells come from a donor, the patient might reject the cells or worse, be at risk for graft-versus-host disease — where contaminating donor cells regard the patient’s body as foreign and attack it. To avoid these problems, the researchers wondered if they could enlist the help of the patients’ own, or autologous, NK cells. Using autologous cells would remove the risks associated with donor cells.

But using autologous cells raised other issues. Would it be possible to multiply NK cells from patients with leukemia, even though they had very few to start with? Also, could the patient’s own NK cells attack their leukemia… and win?

“In this study, we used NK cells and ALL cells from the same pediatric patients. We found that autologous natural killer cells will destroy the patient’s leukemia cells,” said Nora Heisterkamp, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles and one of the co-lead investigators.

To help the NK cells identify their target as leukemia cells, the researchers also added a monoclonal antibody. Antibodies are normally made by cells of the immune system to identify and neutralize foreign material. Researchers can design and produce antibodies, called monoclonal antibodies (mAb), that specifically target a certain protein like the ones found on cancer cells. In a previous paper, Heisterkamp showed that a mAb targeted to a specific receptor (BAFF-R) on the leukemia cells stimulated the NK cells to attack and kill the cancer. The BAFF-R mAb was also used in this study.

“These results are very promising — with potential as a part of first line therapy and also as a treatment for eliminating any remaining cancer cells, known as minimal residual disease, following standard chemotherapy,” said Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles and co-lead investigator on the study. “We anticipate additional pre-clinical testing and then, a clinical trial to evaluate the therapy in children with leukemia.”

source : http://www.sciencedaily.com/releases/2014/08/140819082908.htm

Microchip reveals how tumor cells transition to invasion

Using a microengineered device that acts as an obstacle course for cells, researchers have shed new light on a cellular metamorphosis thought to play a role in tumor cell invasion throughout the body.

The epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, which tend to stick together within a tissue, change into mesenchymal cells, which can disperse and migrate individually. EMT is a beneficial process in developing embryos, allowing cells to travel throughout the embryo and establish specialized tissues. But recently it has been suggested that EMT might also play a role in cancer metastasis, allowing cancer cells to escape from tumor masses and colonize distant organs.

For this study, published in the journal Nature Materials, the researchers were able to image cancer cells that had undergone EMT as they migrated across a device that mimics the tissue surrounding a tumor.

“People are really interested in how EMT works and how it might be associated with tumor spread, but nobody has been able to see how it happens,” said lead author Ian Y. Wong, assistant professor in the Brown School of Engineering and the Center for Biomedical Engineering, who performed the research as a postdoctoral fellow at Massachusetts General Hospital. “We’ve been able to image these cells in a biomimetic system and carefully measure how they move.”

The experiments showed that the cells displayed two modes of motion. A majority plod along together in a collectively advancing group, while a few cells break off from the front, covering larger distances more quickly.

“In the context of cell migration, EMT upgrades cancer cells from an economy model to a fast sports car,” Wong said. “Our technology enabled us to track the motion of thousands of ‘cars’ simultaneously, revealing that many sports cars get stuck in traffic jams with the economy cars, but that some sports cars break out of traffic and make their way aggressively to distant locations.”

Armed with an understanding of how EMT cancer cells migrate, the researchers hope they can use this same device for preliminary testing of drugs aimed at inhibiting that migration. The work is part of a larger effort to understand the underpinnings of cancer metastasis, which is responsible for nine out of 10 cancer-related deaths.

Tumor cells on the move

Time-lapse microphotography shows a portion of the cancer cells making more rapid progress through the cellular obstacle course. Researchers were surprised to observe that cells remaining with the group began reverting to a less invasive cell type.

‘Obstacle course for cells’

To get this new view of how cancer cells move, the researchers borrowed microelectronics processing techniques to pattern miniaturized features on silicon wafers, which were then replicated in a rubber-like plastic called PDMS. The device consists of a small plate, about a half-millimeter square, covered in an array of microscopic pillars. The pillars, each about 10 micrometers in diameter and spaced about 10 micrometers apart, leave just enough space for the cells to weave their way through. Using microscopes and time-lapse photography, the researchers can watch cells as they travel across the plate.

“It’s basically an obstacle course for cells,” Wong said. “We can track individual cells, and because the size and spacing of these pillars is highly controlled, we can start to do statistical analysis and categorize these cells based on how they move.”

For their experiments, the researchers started with a line of benign cancer cells that were epithelial, as identified by specific proteins they express. They then applied a chemical that induced the cells to become malignant and mesenchymal. The transition was confirmed by looking for proteins associated with the mesenchymal cell type. Once all the cells had converted, they were set free on the obstacle course.

The study showed that about 84 percent of the cells stayed together and slowly advanced across the plate. The other 16 percent sped off the front and quickly made it all the way across the device. To the researchers’ surprise, they found that the cells that stayed with the group started to once again express the epithelial proteins, indicating that they had reverted back to the epithelial cell type.

“That was a remarkable result,” Wong said. “Based on these results, an interesting therapeutic strategy might be to develop drugs that downgrade mesenchymal sports cars back to epithelial economy models in order to keep them stuck in traffic, rather than aggressively invading surrounding tissues.”

As for the technology that made these findings possible, the researchers are hopeful that it can be used for further research and drug testing.

“We envision that this technology will be widely applicable for preclinical testing of anti-migration drugs against many different cancer cell lines or patient samples,” Wong said.

Other authors on the paper are Elisabeth A. Wong (no relation), now a medical student at the Alpert Medical School of Brown University, as well as Sarah Javaid, Sinem Perk, Daniel A. Haber, Mehmet Toner, and Daniel Irimia of Massachusetts General Hospital. The work was supported by the Damon Runyon Cancer Research Foundation (DRG-2065-10), the Howard Hughes Medical Institute and the National Institute of Health under (CA129933, EB002503, CA135601, GM092804).

source : http://www.sciencedaily.com/releases/2014/08/140817220021.htm