Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers pinpoint genes that drive spread of breast cancer to lungs

28.07.2005


Search for a special ’genetic endowment’ snares new cancer candidates



Howard Hughes Medical Institute researchers have identified a telltale set of genes that causes breast cancer to spread and grow in the lungs, where cancer cells often flourish with lethal consequences.

The researchers said that the genes are more than markers that identify the presence of metastatic cancer. These genes are mediators that enable fragments of breast cancer tumors to take root in the lungs.


The scientists are hopeful that their research will give clinicians a new set of molecular tools to test tumor biopsies for the activity of these specific genes. This, in turn, should help guide treatment by permitting the early diagnosis of breast cancers that will ultimately metastasize to the lung.

The genes that have been identified produce proteins that may move to the top of the "most wanted list" of prime targets for therapies to thwart metastasis, said the study’s senior author Joan Massagué, a Howard Hughes Medical Institute investigator at Memorial Sloan-Kettering Cancer Center. Massagué and his colleagues are optimistic that their technique can be extended to other types of metastatic cancer, where it should aid in identifying genetic characteristics of metastatic tumors to aid diagnosis and treatment.

Massagué, postdoctoral fellow Andy J. Minn, and graduate student Gaorav P. Gupta, led the research team that published its findings in the July 28, 2005, issue of the journal Nature.

Until now, researchers had taken a largely ad hoc approach to identifying genes that might influence how breast cancer spreads. Such studies usually involved overactivating individual candidate genes and observing whether that change in activity affected the cancer’s ability to spread. Such piecemeal studies did not yield a comprehensive, unbiased picture of the broad genetic changes that drive metastasis, according to Massagué.

More recent advances, including large-scale surveys of gene activity, have revealed that a tumor’s metastatic potential can be identified and defined as a characteristic genetic signature that reflects gene activity in primary tumors. But those techniques only go so far, said Massagué. Those signatures are useful markers of metastasis, but they do not necessarily reveal the identity of specific genes that drive the metastatic process, he said.

In earlier studies in mice, Massagué and his colleagues pioneered a novel approach that led to the identification of a "toolbox" of genes active in metastatic breast cancer cells that help those tumors spread to bone. The new studies reported in Nature build on that earlier work, but with a twist: This time the researchers set out to identify genes that spur metastasis of cancer cells to lung, and to demonstrate that those genes play a role in the establishment of human tumors.

"Reasoning as biologists, we felt that when tumor cells escape into circulation and reach the various organs, these organs are adapted by millions of years of evolution to maintain their integrity and to eliminate those cells," said Massagué. "So, the few metastatic cells that overcome those barriers must have a very special genetic endowment. And since the lung and the bone each impose very strong but different selective pressures, they must be selecting for different genetic abilities. And if this is true, there have to be different sets of active genes for the metastatic cells to survive in each of these organs."

Thus, in their experiments, Massagué and his colleagues injected mice with cultured cells originally taken from the lung of a breast cancer patient with metastatic cancer. They selectively isolated the specific cancer cells from those mice that were distinguished by aggressive lung metastasis. "In essence, we used a mouse as a cell sorter to pinpoint the cancer cells," said Massagué.

Once they had isolated the aggressive metastatic cells, the researchers then analyzed the activity of the cells’ genes using DNA microarrays -- which are capable of measuring the activity of a vast number of genes at once. This analysis revealed a "metastasis signature" of genes whose activity uniquely distinguished the cells that aggressively spread to the lung. Generally, these genes code for proteins that are receptors on the cell surface or external secretory proteins that influence the external "microenvironment" of the cells.

"While our resulting genetic signature correlated very well with the ability of these cells to form metastases in the lungs, the next question was whether these genes were actually mediating that metastasis, or were they simply markers," said Massagué.

The researchers next tested the effects of either overactivating or suppressing the activity of those genes in cancer cells in various combinations. They found that different combinations of those genes did, indeed, profoundly affect that metastatic capacity of those cancer cells in the lungs.

"Up to this point, we had carried the research as far as we had with our previous studies of bone metastasis," said Massagué. "Now, however, we proceeded to explore the effects of these genes in primary human tumors. And that is where we found the most amazing surprise."

In analyzing the genetic signatures produced by tumors that had been excised from 82 patients, the researchers found that those patients whose cancers had metastasized to the lung exhibited the patterns of gene activity characteristic of lung metastasis that they had identified in their cell studies. The researcher also analyzed data from another group of patients in the Netherlands, finding that those patients’ genetic metastasis signature also correlated with lung metastasis in those patients.

According to Massagué, further study of the roles of the metastatic genes indicated that some genes might enhance survival of particular cancer cells in the primary tumor and spread to the lung, while others might afford those cells growth advantages once they take hold in the lung.

"It’s all about selection," said Massagué. "It’s a combination of Darwin and Murphy. These cells are mutating in a largely random fashion, so mutation that gives a cell an advantage will be selected for in a Darwinian manner. And like Murphy’s Law, if a cell can get nasty, it will get nasty."

Studies are now underway to understand the predictive value and function of each of the metastatic genes identified, said Massagué. Once progress has been made on that front, Massagué believes the new knowledge could have profound implications for both diagnosis and treatment of breast cancers.

"Clinicians tell me that the management of a patient who is likely to relapse -- or likely to relapse to the bone versus the lung -- is very different than managing non-relapsing patients," he said. "So at minimum, such knowledge of the likelihood of relapse will help the patient and the physician to be prepared. Also, knowing the organ in which the metastases may recur makes it feasible to follow up more effectively with tests on that patient after removal of the primary tumor, to look for any sign that the tumor is coming back."

In terms of potential for treatments to block metastasis, said Massagué, "Since many of these genes encode receptors or products that the cells secrete, they are pharmacologically more accessible to be blocked than genes whose products act inside the cell. What’s more, compounds already exist to block some of the genes we have identified or the cell functions they regulate. The next step is to begin testing these compounds in animal models to see if they can block metastasis."

More broadly, said Massagué, the technique of isolating metastatic cells and identifying their characteristic genetic signatures can be readily extended to metastasis of breast cancers to other organs, as well as metastasis in other cancers. He and his colleagues are now collaborating with other laboratories to compare the genetic signatures of other cancers that metastasize to the lung.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>