Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Deadly liver cancer may be triggered by cells changing identity, UCSF study shows

17.07.2012
A rare type of cancer thought to derive from cells in the bile ducts of the liver may actually develop when one type of liver cell morphs into a totally different type, a process scientists used to consider all but impossible.

UCSF researchers triggered this kind of cellular transformation—and caused tumors to form in mice—by activating just two genes. Their discovery suggests that drugs that are able to target those genes may provide a way to treat the deadly cancer, known as cholangiocarcinoma. It also shows, yet again, how the process of scientific discovery involves serendipity as well as skill.

The study appears as an advanced online publication July 16, 2012 in the Journal of Clinical Investigation and will appear later in the August print edition.

The two cell types, hepatocytes and biliary cells, exist side by side in the liver, but don't normally change their "stripes" -- their cellular function -- let alone turn into each other. Scientists have therefore assumed that hepatocellular carcinomas, the most common kind of liver cancer, start in the hepatocytes and that cholangiocarcinomas, the bile duct cancers, start in the biliary cells.

Hepatocytes, which form the bulk of the liver, "are very good at making other hepatocytes," said Holger Willenbring, PhD, an associate professor of surgery, a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and a senior author of the study. "They can divide many times but are restricted in the progeny they produce. They either produce more hepatocytes or, if something goes wrong, can cause hepatocellular carcinomas."

The study started when Xin Chen, PhD, an assistant professor of bioengineering and therapeutic sciences and a senior author of the manuscript, tried to make something go wrong in the hepatocytes as a way to explore the origins of hepatocellular carcinoma. Chen and her group hoped to induce the cancer in mice by activating oncogenes, genes that trigger cancer.

Things did go awry in the hepatocytes -- but not in the way the researchers expected. In specific conditions, mice developed cholangiocarcinoma instead of hepatocellular carcinoma. "We were very surprised," Chen recalls. They asked, "How did that happen?"

The two scientists figured some of the genes they had activated might have reprogrammed the hepatocytes in a way that turned them into aberrant biliary cells, capable of forming tumors. Their chief suspects were two genes, NOTCH, which is known to be involved in the embryonic development of bile ducts, and AKT, which has been shown to play a role in many tumors.

The scientists used bits of bacterial DNA called plasmids as delivery vehicles to boost levels of NOTCH and AKT in the liver. Three-and-a-half weeks after injecting these plasmids into mice, small white growths appeared on the surface of their livers and, by five weeks, the tumors had spread through the liver. Now the scientists needed to trace the origins of these cancer cells.

Willenbring's lab had previously developed a method for labeling mouse hepatocytes so that they, and any cell they turned into, would glow. They put this "hepatocyte fate-tracing" system to work and were able to show that the cancerous cells that formed bile duct tumors had in fact started out as hepatocytes.

For many years, scientists had believed that development of cells proceeded in one direction, moving step-by-step from primordial stem cells to fully differentiated adult cells. In recent years, researchers have shown that, by turning on certain genes, mature cells can go back in time to become stem cells or even move sideways to become other kinds of adult cell.

"This highlights how readily one cell can be converted into another and how cancer can do it for you very efficiently," Willenbring said. "For us, it's fairly shocking. It only took two oncogenes and it all happened in a few weeks."

The findings also help explain another puzzle: why the incidence of bile duct cancer is higher in people with hepatitis. "Since hepatitis doesn't do anything to biliary cells that didn't quite make sense," Willenbring said

Now there's a new way to look at it, he suggests. As hepatocytes and their genomes become disarrayed by disease, Willenbring says, they may activate oncogenes in much the same way their experiment did, causing the cells to change identity and become cancerous.

Having shown that NOTCH and AKT are the triggers in this tumor-inducing process, Chen and her team are now hunting for therapies. Working with colleagues from Genentech Inc., they are testing antibodies that may blunt the activity of the genes and halt or reverse the growth of bile duct cancers in mice. "The preliminary results with the therapeutic antibodies are very encouraging," Chen says. If they find the right formula, they may have an answer for a currently untreatable cancer.

Biao Fan, Yann Malato, Diego F. Calvisi, Syed Naqvi, Nataliya Razumilava, Silvia Ribback, Gregory J. Gores, Frank Dombrowski and Matthias Evert contributed to the research.

Funding support came from the California Institute of Regenerative Medicine, National Institutes of Health, Deutsche Forschungsgemeinschaft and the China Scholarship Council.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Follow UCSF
UCSF.edu | Facebook.com/ucsf | Twitter.com/ucsf | YouTube.com/ucsf

Jennifer O'Brien | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Studies and Analyses:

nachricht Do microplastics harbour additional risks by colonization with harmful bacteria?
05.04.2018 | Leibniz-Institut für Ostseeforschung Warnemünde

nachricht Rutgers-led innovation could spur faster, cheaper, nano-based manufacturing
14.02.2018 | Rutgers University

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Structured light and nanomaterials open new ways to tailor light at the nanoscale

23.04.2018 | Physics and Astronomy

On the shape of the 'petal' for the dissipation curve

23.04.2018 | Physics and Astronomy

Clean and Efficient – Fraunhofer ISE Presents Hydrogen Technologies at the HANNOVER MESSE 2018

23.04.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>