Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

It’s not all genetic: Common epigenetic problem doubles cancer risk in mice

25.02.2005


In experiments with mice, a team of scientists from the United States, Sweden and Japan has discovered that having a double dose of one protein is sufficient to change the normal balance of cells within the lining of the colon, thereby doubling the risk that a cancer-causing genetic mutation will trigger a tumor there. Roughly 10 percent of people have this double protein dose as well.



In the Feb. 24 online version of Science, the researchers report that mice engineered to have a double dose of insulin-like growth factor 2 (IGF2) develop more so-called precursor cells within the lining of the colon than normal mice. When these mice also carried a colon-cancer-causing genetic mutation, they developed twice as many tumors as those with normal IGF2 levels, the researchers report. "Both clinically and scientifically, this discovery should expand attention in colon cancer research to earlier events, situations present well before tumors appear," says the study’s leader, Andrew Feinberg, M.D., M.P.H., professor of medicine and director of the Center for Epigenetics in Common Human Disease at Johns Hopkins. "In the mice with a double dose of IGF2, everything is pretty normal except for the extra precursor cells," says Christine Iacobuzio-Donahue, M.D., assistant professor of pathology and oncology. "But when the genetic mutation is present, too, we found a clear cost for what otherwise appears to be a benign effect of extra IGF2."

The team’s analysis of colon tissue samples from a dozen or so Johns Hopkins patients with suspected colon cancer suggests that IGF2’s effect in people may be similar, the researchers report. A larger study of samples from patients with and without suspected colon cancer is underway, Feinberg notes. In the mice -- as well as in about 30 percent of colon cancer patients and 10 percent of the general population -- the extra IGF2 stems not from a genetic problem, or mutation, but an "epigenetic" problem that improperly turns on the copy of the IGF2 gene that should remain off. Unlike most genes, the copy of IGF2 that should be silent depends only on which parent it came from, a situation called genomic imprinting. For IGF2, the copy inherited from the mother is always supposed to be turned off.


In the mice and in some people, however, cells lack the epigenetic "marks" that sit on the DNA and keep the maternally inherited copy turned off. As a result, cells make a double dose of the IGF2 protein and are said to have "loss of imprinting" of IGF2. Although Feinberg and others have already noted an association between loss of imprinting of IGF2 and colon cancer in people, the current experiments were designed to find out whether the loss of imprinting is involved in cancer’s development or just in its progression. "Most researchers, including me, expect epigenetic differences to influence progression -- whether a tumor would grow slowly or quickly, or whether it would spread," says Feinberg. "But, in this case, our results show that loss of imprinting of IGF2 contributes to colon cancer’s development in the mice. It doesn’t cause tumors directly, but it creates an environment which is ripe for cancer to start."

Because precursor cells in the colon’s lining had been identified as a likely starting point for tumors, Feinberg and his team tossed a cancer-causing genetic mutation into the mix. The IGF2 mice were crossed with mice carrying a mutation in a gene called APC, which had been tied to colon cancer by researchers studying families with excessive growths, or polyps, in the colon. Mice with extra IGF2 and the APC mutation developed twice the number of tumors as mice with the mutation but whose IGF2 levels were normal. The tumors grew at the same rate in both sets of mice, suggesting that more tumors get started in the mice with extra IGF2, notes Feinberg. "In the mice, loss of imprinting of IGF2 roughly doubles the risk that the genetic mutation will cause a tumor," says postdoctoral fellow Atsushi Kaneda, Ph.D. "Double the risk may not seem like much, but this loss of imprinting is common."

The researchers’ mice mirror two situations in people because the double dose of IGF2 was accomplished in two ways. One set of mice, obtained from Shirley Tilghman at Princeton, have a double dose of IGF2 because they are missing another gene, H19, whose sequence overlaps the region that usually shuts off one copy of IGF2. As a result, these mice lack H19 and have double IGF2. To isolate the effect of the extra IGF2, Rolf Ohlsson at the Uppsala University, Sweden, developed a set of mice missing only the control region for IGF2; their H19 gene was intact. These mice likely mimic the 30 percent of colon cancer patients and 10 percent or so of the human population who have loss of imprinting of IGF2. Only the Princeton mice have been crossed with the APC mice. Both the Princeton and the Swedish mice have the extra precursor cells in the lining of the colon, suggesting the effect on cancer development would be similar.

Co-author Dan Longo, M.D., of the National Institute on Aging notes that the mice with both double IGF2 and the APC mutation should be a useful animal model to evaluate the impact of colon cancer prevention strategies, including dietary interventions and targeted drugs.

Joanna Downer | EurekAlert!
Further information:
http://www.jhmi.edu
http://www.sciencemag.org

More articles from Life Sciences:

nachricht Unique genome architectures after fertilisation in single-cell embryos
30.03.2017 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

nachricht Transport of molecular motors into cilia
28.03.2017 | Aarhus University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

NASA laser communications to provide Orion faster connections

30.03.2017 | Physics and Astronomy

Reusable carbon nanotubes could be the water filter of the future, says RIT study

30.03.2017 | Studies and Analyses

Unique genome architectures after fertilisation in single-cell embryos

30.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>