Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

MACC1 Gene Is an Independent Prognostic Biomarker for Survival in Klatskin Tumor Patients

31.08.2015

Bile duct cancer is rare and usually detected too late. Often only extensive liver surgery can help or, in rare cases, liver transplantation. But which patients will benefit from surgery and which will not, because their risk of cancer recurrence is too high? With the oncogene MACC1 as a biomarker, physicians for the first time have a tool to decide which treatment option is best for patients with Klatskin carcinoma, one type of bile duct cancer. This result is based on the findings of Andri Lederer and Professor Ulrike Stein of the Experimental and Clinical Research Center (ECRC), an institutional cooperation between the Max Delbrück Center (MDC) and the Charité (Hepatology)*.

The researchers were able to show that if MACC1 expression is low, the patients have a good chance that surgery will prolong survival. By contrast, if the gene is upregulated, the risk of recurrence is high.

The bile ducts are the drainage system for the bile produced by the liver cells. There are bile ducts inside and outside the liver. The bile ducts of the right and left hepatic lobes join to form the common bile duct, which opens into the small intestine (duodenum). There, the bile is required for the digestion of fat.

There are different types of bile duct cancer. One type is Klatskin carcinoma, named after the American internist Gerald Klatskin, which develops just outside the liver. Another type is intrahepatic cholangiocarcinoma (ICC), which starts inside the liver.

Both types of bile duct cancer are rare – in Europe and the U.S. only one in 100 000 people is affected – but they comprise the second most common malignancy of the liver after primary liver cell cancer. Since both Klatskin tumors and ICC are usually detected too late, they are difficult to treat, and patients’ life expectancy is severely reduced. Approximately 30 percent of patients survive the first five years after liver surgery.

In Klatskin tumors, bile flow is obstructed at the confluence (hepatic bifurcation) of the various bile ducts of the liver. Often the carcinoma is so extensive at the time of diagnosis that even a radical removal of the cancer tissue is impossible. In such cases, liver transplantation is the last resort, but it is currently only performed within the framework of clinical trials.

Until now, doctors had no evidence which patients might best be helped with a liver transplant. This decision is made more difficult by the lack of donor organs. Andri Lederer, who worked for a year in the laboratory of Professor Stein at the MDC and who currently works in the Department of General, Visceral and Transplantation Surgery of the Charité under Professor Johann Pratschke, said, “Patients with Klatskin tumors may also benefit from liver transplantation and may live longer, under the condition that they have a low risk of recurrence.”

MACC1 gene highly prognostic for metastasis risk

Using the MACC1 gene as biomarker, physicians can now for the first time determine the risk of metastasis in Klatskin carcinoma. This gene was discovered by Professor Stein, Professor emeritus Peter Schlag (MDC and Charité) and Professor Walter Birchmeier (MDC) in 2009 in tissue samples of colon cancer patients. MACC1 (Metastasis Associated In Colon Cancer 1) not only promotes cancer proliferation but also metastasis formation. The gene is also the main regulator of the HGF/Met signaling pathway. It regulates cell proliferation, cell migration and metastasis formation. Furthermore, in this signaling pathway the Met gene plays an important role in the development of Klatskin carcinoma.

The surgeons Andri Lederer, Professor Daniel Seehofer, Professor Johann Pratschke and Professor Schlag, as well as the pathologist Professor Manfred Dietel and the cancer researcher Professor Stein examined tissue samples from 156 patients with Klatskin and ICC carcinomas, from whom between 1998 and 2003 a part of the liver was removed. Among them were 76 patients with Klatskin carcinomas. The tissue samples contained both malignant tissue as well as cancer-free tissue. Tissue samples from patients with benign liver diseases were also included.

MACC1 expression ten times higher in cancer tissue

The study showed that the MACC1gene is expressed ten times higher in cancer tissue than in normal tissue. Moreover, in recurrent tumors that developed in the patient after surgery, MACC1 expression was much higher than in normal tissue. The survival time of patients with high MACC1 levels amounted on average to a little less than two years (613 days) in contrast to six years (2257 days) for patients with low MACC1. The relapse-free time, i.e. the time without cancer recurrence, in patients with high MACC1 levels was just under two years (753 days) in contrast to almost nine years (3119 days for patients with low MACC1 levels.

However, MACC1 proved unsuitable as a biomarker for intrahepatic cholangiocellular carcinoma (ICC). The researchers hypothesize that ICC and Klatskin carcinomas behave differently, since they originate from different bile ducts inside and outside the liver.

MACC1 – not only a biomarker, but also a target

MACC1 is also responsible for the formation of secondary tumors (distant metastases). The clinicians and researchers therefore view MACC1 not only as an indicator of the severity of a disease, but also as a target for therapy. In preclinical studies, Professor Stein and her colleagues are already testing new substances which inhibit both the expression and the activity of the MACC1 gene.

Blood test for early detection

The earlier a cancer is detected, the greater the chances of successful treatment and a long survival time. Therefore Professor Stein has developed a blood test for early detection of cancer, based on the MACC1 gene. With the blood test, it is possible, at a very early stage of cancer (colon cancer, gastric cancer, lung cancer) to identify patients who are at high risk of developing life-threatening metastases. Meanwhile, the test for the detection of MACC1 in tumors and in blood has been patented in the U.S., Australia, Japan, Canada and Europe.

The aim is to develop such early detection tests with MACC1 for other cancers as well, including the Klatskin carcinoma. Since 2009 Professor Stein and researchers from various countries have shown that there is a correlation in many carcinomas between elevated MACC1 expression and a shorter survival time of the patients. These include liver cancer, stomach cancer, pancreatic cancer, lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, esophageal cancer, kidney cancer, bladder cancer, gallbladder cancer, glioblastoma and bone cancer.

*Hepatology, 2015;62:841-850
MACC1 is an independent prognostic biomarker for survival in Klatskin tumor patients.
Andri Lederer1,2, Pia Herrmann1, Daniel Seehofer2, Manfred Dietel3, Johann Pratschke2, Peter Schlag4,Ulrike Stein1,5.
1Experimental and Clinical Research Center, an institutional cooperation between the Max Delbrück Center for Molecular Medicine, Berlin, Germany and the Charité - Universitätsmedizin Berlin Germany.
2Department of General-, Visceral- and Transplant Surgery, Charité - Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany.
3Department of Pathology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
4Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
5German Cancer Consortium.

Contact:
Barbara Bachtler
Press Department
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Robert-Rössle-Straße 10
13125 Berlin
Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/en

Barbara Bachtler | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft

Further reports about: ICC MACC1 Metastasis Molekulare Medizin Tumor carcinoma carcinomas tumors

More articles from Life Sciences:

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

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...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

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

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>