Featured Research

from universities, journals, and other organizations

Some Brain Tumors May Be Mediated By Tiny Filament On Cells

Date:
August 26, 2009
Source:
University of California - San Francisco
Summary:
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.

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.


Story Source:

The above story is based on materials provided by University of California - San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University of California - San Francisco. "Some Brain Tumors May Be Mediated By Tiny Filament On Cells." ScienceDaily. ScienceDaily, 26 August 2009. <www.sciencedaily.com/releases/2009/08/090823184359.htm>.
University of California - San Francisco. (2009, August 26). Some Brain Tumors May Be Mediated By Tiny Filament On Cells. ScienceDaily. Retrieved September 19, 2014 from www.sciencedaily.com/releases/2009/08/090823184359.htm
University of California - San Francisco. "Some Brain Tumors May Be Mediated By Tiny Filament On Cells." ScienceDaily. www.sciencedaily.com/releases/2009/08/090823184359.htm (accessed September 19, 2014).

Share This



More Health & Medicine News

Friday, September 19, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com
Jury Delivers Verdict in Salmonella Trial

Jury Delivers Verdict in Salmonella Trial

AP (Sep. 19, 2014) A federal jury has convicted three people in connection with an outbreak of salmonella poisoning five years ago that sickened hundreds of people and was linked to a number of deaths. (Sept. 19) Video provided by AP
Powered by NewsLook.com
How The 'Angelina Jolie Effect' Increased Cancer Screenings

How The 'Angelina Jolie Effect' Increased Cancer Screenings

Newsy (Sep. 19, 2014) Angelina's Jolie's decision to undergo a preventative mastectomy in 2013 inspired many women to seek early screenings for the disease. Video provided by Newsy
Powered by NewsLook.com
The Cost of Ebola

The Cost of Ebola

Reuters - Business Video Online (Sep. 18, 2014) As Sierra Leone prepares for a three-day "lockdown" in its latest bid to stem the spread of Ebola, Ciara Lee looks at the financial implications of fighting the largest ever outbreak of the disease. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins