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 New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)

nachricht Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology

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: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

Im Focus: Using graphene to create quantum bits

In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.

In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

Physicists discover mechanism behind granular capillary effect

24.05.2017 | Physics and Astronomy

Measured for the first time: Direction of light waves changed by quantum effect

24.05.2017 | Physics and Astronomy

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>