Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Some brain tumors may be mediated by tiny filament on cells

25.08.2009
UCSF scientists have discovered that a tiny filament extending from cells, until recently regarded as a remnant of evolution, may play a role in the most common malignant brain tumor in children.

The study, conducted in mice and in human brain tissue of medulloblastomas, coincides with a study by another team of UCSF scientists showing that the structure, known as primary cilium, also may play a role in basal cell carcinoma, the most common form of skin cancer. (See related UCSF news release.)

The findings, both reported online on August 23, 2009 in "Nature Medicine," are the first direct evidence of a role of primary cilia in cancer, which the researchers say could lead to a new strategy for diagnosing subtypes of cancers and to potential targets for therapy.

"These findings are very exciting," says the senior of the medulloblastoma study, Arturo Alvarez-Buylla, PhD, UCSF Heather and Melanie Muss Professor of Neurological Surgery and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

"In the last few years, primary cilia have been shown to be essential for the cell-signaling that drives both human development, including the differentiation of stem cells into neurons, and some diseases, including polycystic kidney disease. The fact that the two UCSF studies implicate primary cilia in two totally different tissues suggests the finding is likely to be very general."

Significantly, in both UCSF studies, the findings in mice revealed that primary cilia had opposing roles in cancers depending on which mutated genes initiated the aberrant cell-signaling events to begin with. When one particular mutated protein was activated, removal of the cilium prevented the onset of disease; when another particular gene was activated, absence of the cilium allowed cancers to develop.

Remarkably, an analysis of human tissue in the medulloblastoma study revealed that primary cilia were present in a subset of human tumors, but absent in others. The presence and absence correlated with the cell-signaling pathways that were activated in the tumors. This suggests, the researchers say, that, as in mice, some tumors in humans need to remove the primary cilia to grow, while other require its presence to grow.

The explanation, says the lead investigator of the medulloblastoma study, Young-Goo Han, PhD, a postdoctoral fellow in the Alvarez-Buylla lab, has to do, in part, with the way in which the primary cilium is structured and functions.

Unlike their beating cousins, known as motile cilia, or flagella -- which swish protozoa through pond water and undulate in the airways -- primary cilia are generally immobile, and function as cellular antennae. They receive signals from other cells, allowing for their transmission, in a process known as signal transduction, down a pathway of signaling proteins -- some of which are located precisely in the cilia -- into the cytoplasm, ending at the cell's nucleus, where the signals' commands are issued.

One of the key signaling molecules in development is a secreted lipoprotein known as Hedgehog, which regulates tissue patterning, cell proliferation, and many other biological processes. Recently, scientists have discovered that Hedgehog signaling functions through the primary cilium. As Hedgehog approaches a target cell, it binds to its receptor, Patched1 (Ptch1), on the cilia, opening the gate for another protein, known as Smoothened (Smo) to enter into the cilium. There, Smo, an essential activator of the Hedgehog pathway, initiates the biochemical cascade that leads to the activation of a "downstream" protein known as Gli2, which in part communicates the Hedgehog signal to the cell's nucleus.

Aberrant Hedgehog signaling is well known to lead to human cancers, including basal cell carcinoma and medulloblastoma. However, it was not known if the cilium, itself, played a role in the development of cancers.

Han engineered mice to continuously express a mutant form of Smo, known to cause cancers in humans. In these mice, the mutant form of Smo moved to the cilium, independent of Ptch1, driving the development of medulloblastoma. When Han genetically removed the cilium, no tumors developed.

Predicting that continuously activating a protein in the signaling pathway downstream of Smo and primary cilia would induce tumors whether or not the cilium were present, Han activated Gli2 – and removed the cilium. To the team's astonishment, all of the mice developed medulloblastoma only when primary cilia were removed.

The explanation may be, the researchers say, that removing the primary cilium prevented it from carrying out one of its other jobs – activating proteins in its pathway whose jobs are to suppress Hedgehog signals.

Next, the team examined 38 samples of autopsied brain tissue donated to the UCSF Medical Center Neurological Surgery Tissue Bank and to the Neuropathology Laboratory at St. Jude Children's Research Hospital. Primary cilia were present in most cases of one form of the disease, known as desmoplastic medulloblastoma, and mostly absent in another, known as anaplastic medulloblastoma. Of 24 tissue samples analyzed for their gene-expression profiles, primary cilia were identified almost exclusively in tumors driven by Hedgehog or Wnt signaling.

The findings have prompted the team to begin investigating primary cilia's role not only in other subsets of medulloblastomas but also in glioblastomas, the most common brain tumor in adults, with an eye toward identifying a diagnostic strategy and therapeutic targets.

More broadly, they are considering other questions. Most cells have a primary cilium, notes Alvarez-Buylla. "I think people have paid little attention to this thin, cellular extension or have thought of it just as a remnant of a ciliated organism. It's become clear that it's much more fascinating than that: It may play critical binary roles in many decisions cells make, and may be particularly important in cancer. In some cancers, the activating role of primary cilia is hijacked in order to keep the growth signal on; in other cancers, it is removed to eliminate the off switch."

Co-authors are Hong Joo Kim, UCSF-affiliated Gladstone Institute of Neurological Disease; Andrzej A. Dlugosz, University of Michigan; and David W. Ellison and Richard J. Gilberston, St. Jude Children's Research Hospital.

The study was funded by the National Institutes of Health and the Goldhirsh foundation.

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.

Related links:

Alvarez-Buylla research - UCSF Department of Neurological Surgery http://neurosurgery.ucsf.edu/index.php/about_us_faculty_alvarez_buylla.html

Alvarez-Buylla research - Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF http://stemcell.ucsf.edu/about-us/faculty/bios/alvarez-buylla.aspx

Jennifer O'Brien | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie

nachricht Study overturns seminal research about the developing nervous system
21.04.2017 | University of California - Los Angeles Health Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

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...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, 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

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>