Featured Research

from universities, journals, and other organizations

UCSF-Led Study Points To Pivotal, Early Event In Cancer Development

Date:
February 5, 2001
Source:
University Of California, San Francisco
Summary:
Researchers led by UCSF scientists report that they may have identified a pivotal - and very early -- event in the development of breast cancer, with an unexpected revelation regarding the behavior of mammary epithelial cells. The finding, they say, could point to a new target for very early detection and treatment of breast cancer.

Researchers led by UCSF scientists report that they may have identified a pivotal - and very early -- event in the development of breast cancer, with an unexpected revelation regarding the behavior of mammary epithelial cells. The finding, they say, could point to a new target for very early detection and treatment of breast cancer.

The investigation was conducted in cell culture studies of mammary epithelial cells, in which breast cancer develops. However, because greater than 90 percent of cancers originate in epithelial cells, the finding could have broader implications for understanding carcinogenesis, says the senior author of the study, Thea Tlsty, PhD, UCSF professor of pathology.

The discovery was an outcome of studies supported by the UCSF Breast SPORE (Specialized Program in Organ Research Excellence), a funding mechanism established by the National Cancer Institute aimed at supporting basic scientists in work on translational research.

In their study, the researchers discovered that mammary epithelial cells are unexpectedly prone to spontaneously surmounting a built-in regulatory control on cell growth known as senescence, and that when they do escape this check, they almost always develop the multiple, simultaneous genetic changes associated with the earliest stages of cancer development.

"Until now, we've thought senescence could be relied upon as a barrier to continued cell growth," says Tlsty. "Our cell culture study of mammary epithelial cells suggests otherwise.

"We hypothesize that the mammary epithelial cells escape from senescence and acquire genomic instability to produce the types of genetic changes that occur at the very beginning of breast cancer. Our next step is to determine if these changes take place in animal models. Nobody has understood why the majority of cancer cells are epithelial in origin. This finding offers a possible explanation."

The researchers identified molecular markers that indicate when mammary epithelial cells have escaped senescence, and how far they had progressed toward genomic instability. These markers, they say, could ultimately be used to evaluate the susceptibility of epithelial cells to becoming cancerous and thus point to cells that could be potential targets for prevention and therapy at a precancerous or early cancerous stage.

Cells begin the slide toward the cancerous state when they start to accumulate mutations in the genes involved in regulating a cell's growth. Once enough critical genes have been affected, a cell progressively loses its cell-cycle control, becomes singularly focused on proliferating and eventually breaks out of its tissue membrane. (See image: http://pubaffr.ucsf.edu/imagedb/imsearch.php3?iname=0130200118)

The genesis for the researchers' investigation was, in part, to seek an explanation for why the majority of cancers originate in epithelial cells. They did so by examining and comparing the molecular pathways leading to cancer development in normal fibroblasts -- which make up the connective tissue of the body, including in the breast -- and epithelial cells. Epithelial cells line the outside of the body, the passage ways leading to and from the body's surface, and the portion of the ducts and glands that secrete fluids - including the glands and ductal structures of the breast that develop breast cancer.

While fibroblasts account for some cancers, epithelial cells are the basis of cancers of the breast, prostate, colon and skin, among others.

The researchers placed the two cell types, both derived from normal breast tissue, in separate culture dishes to observe their growth patterns. The differences were quickly apparent.

The fibroblasts displayed the classic characteristics of normal cell behavior. They maintained an active cell cycle for several weeks -- growing, duplicating their DNA and then dividing - and then entered a placid state, or irreversible senescence, characterized by low DNA replication, lack of cell death (indicative of a cell in senescence) and genomic integrity.

The epithelial cells also progressed through cycles of cell division. Then they, too, entered a plateau, in which they displayed the typical characteristics of senescence. The large, flat cells filled the petri dish, their DNA in a semi somnolent state, their genes stable, with little cell death occurring.

But then, the researchers observed a startling phenomenon - after 10 days to two weeks, a surprisingly high number of cells began to emerge from this plateau. Small cells started to grow out atop the broad, dormant cells, and eventually these emerging colonies overtook the culture. They grew for several more months - through another 50 cycles of cell division -- and then entered a second plateau.

Researchers already knew that epithelial cells occasionally overrode the initial plateau, but previous studies had not identified the plateau as senescence. They also thought that those cells that did emerge were normal and that, in these cases, they entered genuine senescence at the second plateau. But the UCSF-led team's observations suggested otherwise.

The investigators determined that a relatively high number of cells spontaneously emerged from the plateau, that many of these cells proliferated abundantly and that greater than 90 percent progressively acquired genetic mutations. As they approached the second plateau, they displayed the genomic instability associated with the earliest steps of cancer.

Finally, the researchers determined that the second plateau wasn't senescence at all - the cells at this stage displayed continuous cell proliferation, abundant cell death (indicative of cells in crisis), and severe structural abnormalities in the chromosomes, which contain the genes, that are seen in the earliest lesions of breast cancer.

"This is what you see in cell culture when you treat cells with viral oncoproteins, but these events were occurring in cells without any mutagens or viruses," says Tlsty.

Events traditionally recognized as contributing to the development of genetic mutations include genetic inheritance, haphazard missteps during the cell cycle, environmental factors such as diet, physical agents, such as ultra violet rays, and viral and chemical mutagenic agents.

The discovery that a cell-intrinsic mechanism could be paving the way for carcinogenesis challenges the traditional view of how and when cells acquire genomic changes in cancer, says Tlsty.

"Figuring out why mutations occur -- never mind what they actually are - could provide a new means for intercepting the disease before it gets started," she says.

The current finding could put them on track.

Co-authors of the study were lead author Serguei R. Romanov, PhD, formerly a post-doctoral fellow in the Tlsty lab, now at University of North Carolina; B. Krystyna Kozakiewicz, PhD, UCSF senior research associate, Charles R. Holst, a graduate student in the Tlsty lab; Larisa M. Haupt, PhD, a postdoctoral fellow in the Tlsty lab, and Martha R. Stampfer, PhD, a senior scientist at Lawrence Berkeley National Laboratory.

The study was funded by the National Institutes of Health, the National Aeronautics and Space Administration and the Department of Energy and the UCSF Breast SPORE.


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. "UCSF-Led Study Points To Pivotal, Early Event In Cancer Development." ScienceDaily. ScienceDaily, 5 February 2001. <www.sciencedaily.com/releases/2001/02/010205074850.htm>.
University Of California, San Francisco. (2001, February 5). UCSF-Led Study Points To Pivotal, Early Event In Cancer Development. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2001/02/010205074850.htm
University Of California, San Francisco. "UCSF-Led Study Points To Pivotal, Early Event In Cancer Development." ScienceDaily. www.sciencedaily.com/releases/2001/02/010205074850.htm (accessed September 1, 2014).

Share This




More Health & Medicine News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Get on Your Bike! London Cycling Popularity Soars Despite Danger

Get on Your Bike! London Cycling Popularity Soars Despite Danger

AFP (Sep. 1, 2014) Wedged between buses, lorries and cars, cycling in London isn't for the faint hearted. Nevertheless the number of people choosing to bike in the British capital has doubled over the past 15 years. Duration: 02:27 Video provided by AFP
Powered by NewsLook.com
Can You Train Your Brain To Eat Healthy?

Can You Train Your Brain To Eat Healthy?

Newsy (Sep. 1, 2014) New research says if you condition yourself to eat healthy foods, eventually you'll crave them instead of junk food. Video provided by Newsy
Powered by NewsLook.com
We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
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