Featured Research

from universities, journals, and other organizations

Tissue Stiffness Drives Tumor Formation

Date:
September 27, 2005
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers at the University of Pennsylvania School of Medicine have shown that tumor formation is generated by a complex interaction of both mechanical as well as chemical signals, and the resulting tissue stiffening induces molecular signals that promote the cancerous behavior of cells. Force, growth, and tumor behavior are inextricably linked and this enhanced understanding of the necessary fusion of these factors may lead to the development of new tumor therapies or targets.

Extracellular matrix stiffness influences tissue growth and changes in function by modulating cell contractility. For example, as stiffness increases in connective tissue, the cells of a normal breast duct (panel 1) start to behave aberrantly, causing the structure of the duct to degrade (panel 2), as the uncontrolled cell growth of duct-lining cells invade the duct tube (panel 3).
Credit: Matthew Naszek, University of Pennsylvania School of Medicine and Cell Press

(Philadelphia, PA) - The relationship betweentissue rigidity and tumor formation is fairly well established;however, what is not so well understood is what happens on a molecularlevel that contributes to such stiffness. Now, for the first time,researchers at the University of Pennsylvania School of Medicine haveshown that tumor formation is generated by a complex interaction ofboth mechanical as well as chemical signals, and the resulting tissuestiffening induces molecular signals that promote the cancerousbehavior of cells. Penn's interdisciplinary research team-drawn fromthe fields of Biomedical Engineering and Cell and DevelopmentalBiology-has demonstrated clearly that force, growth, and tumor behaviorare inextricably linked and this enhanced understanding of thenecessary fusion of these factors may lead to the development of newtumor therapies or targets.

"This study identifies the connection between oncogenes and themechanics of the cell and its microenvironment in animal and cultureexperimental models," explains senior author Valerie Weaver, PhD,Assistant Professor of Pathology and Laboratory Medicine."Specifically, we have defined the vitality of mechanical force as anintegral factor in tumor development." Weaver and colleagues publishedtheir findings as the cover-story in the September issue of CancerCell.

Weaver and first authors, Matthew J. Pascek and NastaranZahir-both graduate students in Bioengineering-used a three-dimensionalgel on which they grew breast cancer cells and could precisely controland measure the stiffness of the surrounding microenvironment. "Wefound that tissue rigidity enhances cell growth and destroys tissueorganization to promote tumor-like behavior in normal cells," saysPascek. "This happens because the stiffness helps to activate keygrowth signaling pathways and increase cell tension."

Cells use surface receptors called integrins to communicatewith the outside tissue environment, which consists primarily ofconnective tissue. Integrins regulate cell growth, death, and movement,as well as tissue organization. Integrins also play a role in celldivision and proliferation through ERK, an extracellularsignal-regulating molecule. Despite the fact that integrins werediscovered and their activity found to be aberrant in tumors decadesago, how integrins could become altered and their importance to cancerhas remained contentious among researchers.

Weaver and colleagues found that tissue stiffness inducestumor-like behavior in cells through ERK and Rho, another regulatorymolecule. Although researchers have long appreciated that oncogenessuch as Ras and Erb2 drive cell growth via the ERK pathway, this studyshowed how high levels of ERK also prime a cell to contract more viaintegrins.

Integrin activity also regulates the Rho molecular pathway,which in tumors regulates the stiffness of the cytoskeleton, acollection of protein filaments within a cell that give shape and thecapacity for directed movement. When the researchers increased thestiffness of the gel in which experimental cells were grown, Rhoactivity increased, as well as the number and size of focal adhesions,clusters of integrins that create a connection between integrins andthe cytoskeleton.

Overall, the researchers found that a self-perpetuating programof tissue destruction is set up-through changed integrin signaling-tocreate a double-pronged drive toward aberrant cell behavior. Both thestiffness of connective tissue surrounding developing tumors and theincreased activity or expression of oncogenes can promote cells tobecome cancerous. For example, the researchers found that as stiffnessincreased in connective tissue, the cells of a normal breast ductstarted to grow atypically, causing the structure of the duct todegrade, as the uncontrolled cell growth of duct-lining cells invadedthe duct tube.

The researchers also discovered that when cell tension becomesgreat enough, it overrides normal tissue behavior, but is reversible."We showed that some breast tumors with elevated signaling for thegrowth factor ERK also have high tension and that their behavior wouldreturn to normal by inhibiting cell tension," says Zahir. With thisknowledge, Weaver's group is now looking to see whether drugs thatinhibit cell contractility could help prevent early metastasis. Theyare also fine-tuning how different cell types react to different levelsof stiffness and how this is important for normal cell behavior, aswell as aberrant activity and structure.

###

This research was funded by the Department of Defense and theNational Institutes of Health. Co-authors are Kandice R. Johnson,Johnathon N. Lakins, Gabriela I. Rozenberg, Amit Gefen, Cynthia A,Reinhart-King, Susan S. Margulies, David Boettinger, and Daniel A.Hammer, all from Penn; as well as Mica Dembo from Boston University.


Story Source:

The above story is based on materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

University of Pennsylvania School of Medicine. "Tissue Stiffness Drives Tumor Formation." ScienceDaily. ScienceDaily, 27 September 2005. <www.sciencedaily.com/releases/2005/09/050926082535.htm>.
University of Pennsylvania School of Medicine. (2005, September 27). Tissue Stiffness Drives Tumor Formation. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2005/09/050926082535.htm
University of Pennsylvania School of Medicine. "Tissue Stiffness Drives Tumor Formation." ScienceDaily. www.sciencedaily.com/releases/2005/09/050926082535.htm (accessed July 29, 2014).

Share This




More Health & Medicine News

Tuesday, July 29, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Ebola Virus Threatens West Africa

Deadly Ebola Virus Threatens West Africa

AP (July 28, 2014) West African nations and international health organizations are working to contain the largest Ebola outbreak in history. It's one of the deadliest diseases known to man, but the CDC says it's unlikely to spread in the U.S. (July 28) Video provided by AP
Powered by NewsLook.com
$15B Deal on Vets' Health Care Reached

$15B Deal on Vets' Health Care Reached

AP (July 28, 2014) A bipartisan deal to improve veterans health care would authorize at least $15 billion in emergency spending to fix a veterans program scandalized by long patient wait times and falsified records. (July 28) Video provided by AP
Powered by NewsLook.com
Two Americans Contract Ebola in Liberia

Two Americans Contract Ebola in Liberia

Reuters - US Online Video (July 28, 2014) Two American aid workers in Liberia test positive for Ebola while working to combat the deadliest outbreak of the virus ever. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
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