Navigation Links
Wistar researchers show targeting 'normal' cells in tumors slows growth
Date:11/16/2009

Targeting the normal cells that surround cancer cells within and around a tumor is a strategy that could greatly increase the effectiveness of traditional anti-cancer treatments, say researchers at The Wistar Institute.

In the Journal of Clinical Investigation published online November 16, they demonstrate the critical role for fibroblast activation protein (FAP), expressed by one type of these so-called "stromal" cells, in promoting tumor growth in mice. Genetically deleting or therapeutically targeting FAP significantly reduced the rate of tumor growth in mice by interrupting or blocking important signaling pathways and biological processes required for tumor growth, the Wistar team found.

"It's like taking away the soil from a seed that wants to grow," says senior author Ellen Pur, Ph.D., a professor in the Molecular and Cellular Oncogenesis Program at Wistar. "These results provide a proof-of-principle that targeting and modifying a tumor's microenvironment may be an effective approach to treating solid tumors."

Tumors are a complex mix of neoplastic cancer cells and normal cells inflammatory and immune cells, endothelial cells, fibroblasts, pericytes, and others, collectively known as stromal cells. In addition, a web-like extracellular matrix is created by the stromal cells, and its structure is important for supporting and nurturing tumor growth through molecular signaling pathways.

The Wistar team focused on fibroblasts and pericytes. In addition to synthesizing components of the extracellular matrix, fibroblasts associated with tumors also express FAP, a particular protease that cuts up other proteins while pericytes are important to the function of the new blood vessels that develop in tumors. FAP is expressed in 90 percent of all human epithelial (solid) cancers, and FAP expression is recognized as a marker for and is thought to play a role in cancer growth, but the mechanisms through which this occurs had been previously unknown.

"Our data clearly demonstrate that FAP indeed promotes the growth of colon cancer as well as lung cancer in animal models, and provide insight into how FAP works," says Pur. To explore how FAP promotes tumor growth, lead author Anglica Santos, Ph.D., and colleagues took two approaches genetic deletion and pharmacologic targeting of FAP to determine the effects of deactivating FAP in mouse models of lung and colon cancer.

First, they examined the genetic deletion of FAP. In collaboration with Wistar assistant professor and co-author Joseph Kissil, Ph.D., they mated mice engineered to spontaneously develop lung cancer when their K-Ras gene is activated with mice whose FAP gene had been deleted to develop a new strain of mice with a genetic deletion of FAP and expressing an activated K-Ras gene.

The Wistar team found that lung tumor growth was substantially inhibited in these mice. In another experiment the investigators transplanted colon cancer cells into FAP-deficient mice and saw a similarly marked inhibition of tumor growth.

"We found that FAP inactivation disrupts the organization of the collagen fibers which are a key component of matrix and that could be critical for many things, including cell to cell communication, cell-matrix interactions and development of new blood vessels to feed the tumors," Pur says. "The organization or architecture of the matrix is important to supporting both stromal and cancer cells within a tumor. If stromal cells depend on this matrix for structural support and to communicate with the cancer, they can't do that properly if it is drastically modified as we observed in the absence of FAP activity. "

To explore the potential for a therapeutic approach, the investigators used a novel peptide agent, PT630, to shut down FAP activation in the lung and colon cancer mice. Again, they found a significant reduction in tumor growth by inhibiting the enzymatic activity of FAP with this candidate drug agent.

"This proof of concept is the first step toward the clinic," Pur says. "We need more drugs that target the non-cancer cells in tumors, which can then be combined with specific chemotherapies and biologic drugs to attack both the tumor and its supporting cells."

One of the benefits of such a strategy, Pur adds, is that a limited number of agents would likely be required to treat many different cancers, because stromal cells tend to have common properties and share expression of the FAP protein in most tumor types. Comparatively, targeted therapies designed for specific tumor types such as breast or colon will likely require a wide variety of different drugs.

The only agents currently used to treat cancer by targeting the tumor microenvironment are anti-angiogenesis drugs, like Avastin, which disrupt blood vessel formation to tumors.


'/>"/>

Contact: Staci Vernick Goldberg
sgoldberg@wistar.org
215-898-3716
The Wistar Institute
Source:Eurekalert

Related medicine news :

1. Novel vaccine concept developed by scientists at the Wistar Institute
2. The Wistar Institute collaborates with the Coriell Institute to distribute cell lines
3. Los Angeles Times writer wins Wistar Institute Science Journalism Award
4. Wistar Institute team finds key target of aging regulator
5. Stanford researchers find culprit in aging muscles that heal poorly
6. UCLA researchers identify markers that may predict diabetes in still-healthy people
7. Mayo Clinic researchers discover new diagnostic test for detecting infection in prosthetic joints
8. Bipolar disorder relapses halved by Melbourne researchers
9. Cell that triggers symptoms in allergy attacks can also limit damage, Stanford researchers find
10. High and mighty: first common height gene identified by researchers behind obesity gene finding
11. Researchers estimate about 9 percent of US children age 8 to 15 meet criteria for having ADHD
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/26/2017)... ... , ... Amir Qureshi, MD is the first physician in Arkansas to implant ... The Nuvectra™ Algovita SCS System has been FDA approved as a treatment option for ... to introduce the most powerful SCS system and the only stretchable lead on the ...
(Date:5/26/2017)... ... May 26, 2017 , ... A new analysis of community health data ... are located in the Midwest. With the average cost of healthcare rising and the ... with both the quality and affordability of where they live. An annual 2017 report ...
(Date:5/26/2017)... ... May 26, 2017 , ... via seating is proud to ... task chair specifically designed for clinical areas. Genie Copper Mesh is a crossover ... Cupron® to provide customers with a game changing chair that is affordably priced,” ...
(Date:5/26/2017)... ... ... After raising nearly $30,000 on Kickstarter , about three-times its original campaign ... crowdfunding price on Indiegogo . , “Along with creating an anti-stress gadget to ... fidget toy to the market that was made of superior quality and wouldn’t break ...
(Date:5/26/2017)... (PRWEB) , ... May 26, 2017 , ... Silver Birch ... community, which is located on more than four acres of land at 5620 Sohl ... , The 103,000 square-foot building includes 125 studio and one-bedroom apartments. Each of ...
Breaking Medicine News(10 mins):
(Date:5/6/2017)... , May 5, 2017   Provista , a proven ... than 200,000 customers, today announced Jim Cunniff as ... of executive and business experience to Provista, including most recently ... in California . He assumed his new ... is a great fit for Provista," says Jody Hatcher ...
(Date:5/4/2017)... Tenn. , May 4, 2017  A ... Infection Control, Ultraviolet-C light as a ... Tru-D SmartUVC,s ability to reduce bioburden on anesthesia ... bioburden reduction on high-touch, complex medical equipment surfaces ... surgical infections. "This study further validates ...
(Date:5/4/2017)... May 4, 2017  A new tight-tolerance microextrusion ... other highly-engineered materials, is being launched by Natvar, ... been developed in recent years to service a ... surgical applications. More expensive materials such as glass ... tubing due to their ability to consistently hold ...
Breaking Medicine Technology: