PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

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

2012-07-17
(Press-News.org) 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

END



ELSE PRESS RELEASES FROM THIS DATE:

Force of nature: Defining the mechanical mechanisms in living cells

2012-07-17
VIDEO: This brief video shows a cell division within a tissue and the mechanical forces clearly at play in the cell's placement in the tissue. Click here for more information. If you place certain types of living cells on a microscope slide, the cells will inch across the glass, find their neighbors, and assemble themselves into a simple, if primitive tissue. A new study at Stanford University may help explain this phenomenon, and then some, about the mechanical structure ...

Mayo Clinic begins to unravel rare heart condition that strikes young, healthy women

2012-07-17
ROCHESTER, Minn. -- Spontaneous coronary artery dissection (SCAD), a tear of the layers of the artery wall that can block normal blood flow into and around the heart, is a relatively rare and poorly understood condition. It often strikes young, otherwise healthy people -- mostly women -- and can lead to significant heart damage, even sudden death. Now, in the first study of its kind of such patients, Mayo Clinic researchers have started to uncover important clues about SCAD, including its potential risk factors, optimal treatment approaches and short- and long-term cardiovascular ...

US Army: Pre-injury cartilage biomarkers associated with subsequent ACL injuries

2012-07-17
Baltimore, Md., July 16, 2012 – U.S. Army researchers made a surprising discovery while examining the impact of an anterior cruciate ligament (ACL) tear (a common knee injury), on four serum biomarkers associated with cartilage health. The researchers found that pre-injury concentrations for all but one of the four serum biomarkers studied were associated with the subsequent likelihood of ACL injury. The findings were presented Saturday at the annual meeting of the American Orthopaedic Society for Sports Medicine (AOSSM). "We expected to see post-injury differences in ...

Increase in RDA for vitamin C could help reduce heart disease, stroke, cancer

2012-07-17
CORVALLIS, Ore. – The recommended dietary allowance, or RDA, of vitamin C is less than half what it should be, scientists argue in a recent report, because medical experts insist on evaluating this natural, but critical nutrient in the same way they do pharmaceutical drugs and reach faulty conclusions as a result. The researchers, in Critical Reviews in Food Science and Nutrition, say there's compelling evidence that the RDA of vitamin C should be raised to 200 milligrams per day for adults, up from its current levels in the United States of 75 milligrams for women and ...

RIH study: Emergency patients prefer technology-based interventions for behavioral issues

2012-07-17
PROVIDENCE, R.I. – A Rhode Island Hospital researcher has found that emergency department patients prefer technology-based interventions for high-risk behaviors such as alcohol use, unsafe sex and violence. ER patients said they would choose technology (ie text messaging, email, or Internet) over traditional intervention methods such as in-person or brochure-based behavioral interventions. The paper by Megan L. Ranney, M.D., is available now online in advance of print in the Annals of Emergency Medicine. The study was a cross-sectional survey of urban emergency department ...

Uncommon BRAF mutation in melanoma sensitive to MEK inhibitor drug therapy

2012-07-17
An uncommon mutation of the BRAF gene in melanoma patients has been found to respond to MEK inhibitor drugs, providing a rationale for routine screening and therapy in melanoma patients who harbor the BRAF L597 mutation. The new study by co-first-authors Kimberly Brown Dahlman, Ph.D., Junfeng Xia, Ph.D., and Katherine Hutchinson, B.S., Vanderbilt-Ingram Cancer Center (VICC), Nashville, Tenn., was published online July 14 in Cancer Discovery. The research was led by co-senior authors William Pao, M.D., Ph.D., Jeffrey Sosman, M.D., and Zhongming Zhao, Ph.D., VICC, and ...

Low-cal diet's effects seen in fly brain, mouthpart

2012-07-17
SAN ANTONIO (July 16, 2012) — A novel technique for measuring tiny, rapid-fire secretions in the brains and mouthparts of fruit flies (drosophila) is providing insights into the beneficial effects of eating less — information that ultimately could help people suffering from neuromuscular disorders. Using the method, researchers uncovered never-before-seen brain chemistry that helps explain why fruit flies genetically manipulated to mimic conditions such as Parkinson's disease and myasthenia gravis are more vigorous and live longer when fed a restricted diet. Published ...

Gene therapy treatment extends lives of mice with fatal disease, MU study finds

2012-07-17
COLUMBIA, Mo. — A team of University of Missouri researchers has found that introducing a missing gene into the central nervous system could help extend the lives of patients with Spinal Muscular Atrophy (SMA) – the leading genetic cause of infantile death in the world. SMA is a rare genetic disease that is inherited by one in 6,000 children who often die young because there is no cure. Children who inherit SMA are missing a gene that produces a protein which directs nerves in the spine to give commands to muscles. The MU team, led by Christian Lorson, professor in ...

U of S researchers discover cannabis 'pharma factory'

2012-07-17
U of S researchers have discovered the chemical pathway that Cannabis sativa uses to create bioactive compounds called cannabinoids, paving the way for the development of marijuana varieties to produce pharmaceuticals or cannabinoid-free industrial hemp. The research appears online in the July 16 early edition of the Proceedings of the National Academy of Sciences (PNAS). U of S adjunct professor of biology Jon Page explains that the pathway is an unusual one, involving a specialized version of one enzyme, called hexanoyl-CoA synthetase, and another enzyme, called olivetolic ...

Victory stance may be a universal gesture of triumph -- not pride -- study suggests

2012-07-17
When Olympic athletes throw up their arms, clench their fists and grimace after a win, they are displaying triumph through a gesture that is the same across cultures, a new study suggests. New findings due to be published in the journal Evolution and Human Behavior suggest this victory pose signals feelings of triumph, challenging previous research that labeled the expression pride. "We found that displays of triumph include different behaviors to those of pride and occur more immediately after a victory or win," said David Matsumoto, professor of psychology at San Francisco ...

LAST 30 PRESS RELEASES:

Mysterious ‘Dark Dwarfs’ may be hiding at the heart of the Milky Way

Real-world data shows teclistamab can benefit many multiple myeloma patients who would have been ineligible for pivotal trial

Scientists reveal how a key inflammatory molecule triggers esophageal muscle contraction

Duration of heat waves accelerating faster than global warming

New mathematical insights into Lagrangian turbulence

Clinical trials reveal promising alternatives to high-toxicity tuberculosis drug

Artificial solar eclipses in space could shed light on Sun

Probing the cosmic Dark Ages from the far side of the Moon

UK hopes to bolster space weather forecasts with Europe's first solar storm monitor

Can one video change a teen's mindset? New study says yes - but there’s a catch

How lakes connect to groundwater critical for resilience to climate change, research finds

Youngest basaltic lunar meteorite fills nearly one billion-year gap in Moon’s volcanic history

Cal Poly Chemistry professor among three U.S. faculty to be honored for contributions to chemistry instruction

Stoichiometric crystal shows promise in quantum memory

Study sheds light on why some prostate tumors are resistant to treatment

Tree pollen reveals 150,000 years of monsoon history—and a warning for Australia’s northern rainfall

Best skin care ingredients revealed in thorough, national review

MicroRNA is awarded an Impact Factor Ranking for 2024

From COVID to cancer, new at-home test spots disease with startling accuracy

Now accepting submissions: Special Collection on Cognitive Aging

Young adult literature is not as young as it used to be

Can ChatGPT actually “see” red? New results of Google-funded study are nuanced

Turning quantum bottlenecks into breakthroughs

Cancer-fighting herpes virus shown to be an effective treatment for some advanced melanoma

Eliminating invasive rats may restore the flow of nutrients across food chain networks in Seychelles

World’s first: Lithuanian scientists’ discovery may transform OLED technology and explosives detection

Rice researchers develop superstrong, eco-friendly materials from bacteria

Itani studying translation potential of secure & efficient software updates in industrial internet of things architectures

Elucidating the source process of the 2021 south sandwich islands tsunami earthquake

Zhu studying use of big data in verification of route choice models

[Press-News.org] Deadly liver cancer may be triggered by cells changing identity, UCSF study shows