Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Identify Distinctive Signature for Metastatic Prostate Cancer

14.09.2004


Howard Hughes Medical Institute researchers have identified a telltale change in cellular machinery that could help clinicians predict whether prostate cancers are likely to spread or remain relatively harmless in the prostate.



The researchers found that a cellular signaling molecule called Hedgehog, which drives normal development and regeneration of prostate tissue, is greatly activated in prostate cancers. This elevated activity distinguishes dangerous metastatic cancers - those that are likely to spread - from those that remain benign and localized to the prostate.

Prostate cancer is the second leading cause of cancer death in men, and an estimated 230,000 cases will be diagnosed this year, according to the American Cancer Society. Treatment for prostate cancer can cause significant side effects, including sexual and urinary dysfunction, yet may not be needed for men whose cancers are unlikely to spread.


The researchers’ findings were published September 12, 2004, in an advance online publication in the journal Nature. The scientists were led by Howard Hughes Medical Institute (HHMI) investigator Philip A. Beachy and his colleagues at The Johns Hopkins University School of Medicine, Drs. David Berman and Sunil Karhadkar. Additional coauthors included other colleagues at Johns Hopkins and a researcher from the U.S. Department of Agriculture.

“These findings quite unexpectedly extend understanding of the Hedgehog pathway to a role in prostate cancer, which is a major form of cancer,” commented molecular oncologist Charles Sawyers, an HHMI investigator at the Jonsson Comprehensive Cancer Center at UCLA. “The results are incredibly interesting, because they are among the most promising I’ve seen to enable distinguishing good-risk cancers from bad-risk cancers - and thus, those that need minimal therapy from those that are lethal.”

The Hedgehog signaling pathway is a well-known regulator of organ development. Beachy and his colleagues, as well as researchers at other institutions, have found that in some cancers, this pathway has escaped the normal control mechanisms and helped spur uncontrolled cell proliferation. These include cancers arising in organs of the gastrointestinal tract, such as the stomach, pancreas, esophagus and biliary tract.

According to Beachy, since all these cancers arise in organs of endodermal origin, it seemed reasonable to test whether activation of the Hedgehog pathway might similarly drive the development of prostate cancer, which also arises from endodermal tissues.

In their initial studies, Beachy and his colleagues established that the Hedgehog pathway was, indeed, active in cultures of human metastatic prostate cancer cell lines. Blocking Hedgehog signaling with cyclopamine, a drug discovered by Beachy’s group that targets another protein in the pathway, Smoothened, inhibited growth of these cell lines. Furthermore, they showed that when the tumor cells were introduced into mice, cyclopamine caused a permanent regression of the tumors.

“We interpreted the finding in mice to mean that we had probably killed tumor stem cells responsible for propagating the cancers,” said Beachy. “This finding led us to explore the role that the Hedgehog pathway might play in the function of normal progenitor cells.”

To study the relationship of the Hedgehog pathway to normal prostate stem cells, the researchers performed experiments in mice in which they eliminated the male hormone, androgen, causing regression of the prostate. Normally, restoring androgen causes the prostate to regenerate. However, the scientists were able to block this regeneration by giving the animals cyclopamine or a Hedgehog-neutralizing antibody.

In additional studies of cultures of cells that closely resemble these prostate progenitor cells, the researchers found that switching on the Hedgehog pathway caused them to proliferate and form tumors when implanted into mice.

“This was a very striking observation, because it’s very tough with manipulation of expression of a single cellular gene - and has never been done before, to my knowledge - to cause a primary human cell to become a cancer,” said Beachy. “And that suggests that perhaps we have identified the right prostate target cell and activated the right pathway to trigger cancerous growth.”

To relate their findings to the metastatic process, the researchers tested samples of metastatic prostate cancer from men who had died of the disease. They found a uniformly high level of Hedgehog activity in these tissues, compared to benign prostate tissue samples. The researchers also found high levels of Hedgehog pathway activity in rat prostate cancer cells known to be actively metastatic.

In contrast, cells that were not metastatic showed low levels of activity. In particular, said Beachy, their experiments showed that pathway activation in metastatic cancers depended on the expression of Smoothened - suggesting that gene may be “a focal point of regulation in tissue regeneration and tumorigenesis.”

They also found they could convert low-metastatic cells into highly metastatic tumors by activating the Hedgehog pathway. “We actually found we could interconvert the two kinds of cell lines in mice,” said Beachy. “Whereas the high-metastatic lines were normally rapidly lethal in the mice, we could prolong survival essentially indefinitely by giving them cyclopamine. And when we activated Hedgehog in the low-metastatic lines, they became highly lethal,” he said.

HHMI investigator Matthew Scott, a developmental biologist who has studied the Hedgehog pathway at Stanford University, noted that Beachy’s “study is very thoroughly done and holds great promise in the search for new treatments for human disease. Quite possibly only some of the cells in a tumor - "tumor stem cells" - have the especially dangerous property of unlimited growth, so the search for ways to identify such cells is important,” he said.

According to Beachy, both diagnosis and treatment of prostate cancer could benefit from understanding the role of Hedgehog activation in carcinogenesis. “If clinicians could use Hedgehog activation - perhaps measured by detecting some marker in the blood - to distinguish indolent from metastatic disease, they could know to treat the metastatic form and not the indolent form,” he said. “If the indolent form, for example, were detected in older men, it might not be as necessary to perform a prostatectomy, since there would be little likelihood of metastasis.

“This finding also suggests that it may be possible to treat the metastatic disease with inhibitors of the Hedgehog pathway,” said Beachy. “However, given the broad importance of this pathway, there are questions of unwanted side effects. We have been able to give effective doses of cyclopamine to mice for long periods of time without any obvious detriment. But we have no idea whether there are long-term physiological effects, or whether humans might suffer side effects that we could not detect in animals.”

Jennifer Michalowski | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>