Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Changing cancer's environment to halt its spread

22.05.2013
Study clarifies roles of anti-angiogenic proteins in discouraging metastasis and reveals potential anti-metastasis drug

By studying the roles two proteins, thrombospondin-1 and prosaposin, play in discouraging cancer metastasis, a trans-Atlantic research team has identified a five-amino acid fragment of prosaposin that significantly reduces metastatic spread in mouse models of prostate, breast and lung cancer. The findings suggest that a prosaposin-based drug could potentially block metastasis in a variety of cancers.

The study team, led by Randolph Watnick, PhD, at Boston Children's Hospital, Vivek Mittal, PhD, at Weill Cornell Medical College and Lars Akslen, MD, PhD, at the University of Bergen, released their findings in the May issue of the journal Cancer Discovery.

The main cause of cancer mortality is not the primary tumor itself, but rather its spread—metastasis—to other locations in the body and subsequent organ failure. Previous studies by Watnick, a member of Boston Children's Vascular Biology Program, and others have shown that tumors capable of metastasis release proteins that help prepare new homes in distant organs for their metastatic progeny.

Watnick's lab has also previously shown that tumors that cannot metastasize release prosaposin. This protein activates expression of a second protein called thrombospondin-1, a potent anti-angiogenic factor, in tissues where metastatic tumor cells could potentially take root. Thrombospondin-1 makes these otherwise-permissive tissues resistant to metastasis.

"In the past, we've struggled to determine the source of thrombospondin-1 production," Watnick says. "We knew it was coming from the tumor microenvironment, normal cells adjacent to the sites of potential metastasis, but we could not tell if those cells were native to the microenvironment or had been recruited from the bone marrow."

Using mouse models of breast, prostate and lung cancer, Watnick and his colleagues confirmed through bone marrow transplant and gene knockout experiments that both metastatic and non-metastatic tumors induce cells from the bone marrow—specifically, monocytes expressing the Gr1 surface marker—to migrate to the lungs. However, non-metastatic tumors then trigger these monocytes to produce thrombospondin-1 by releasing prosaposin.

"Others have shown that tumors recruit monocytes to future metastatic sites, which help to set up a permissive environment for tumor cells to metastasize, " Watnick notes. "Our results suggest that non-metastatic tumors do the same thing, but instead of creating a permissive environment, the monocytes create a refractory environment by producing thrombospondin-1."

Watnick thinks this finding creates a window of therapeutic opportunity. "If we can trigger monocytes recruited by pro-metastatic tumors to produce thrombospondin-1 like those recruited by non-metastatic tumors, we will be able to hijack the mechanism by which tumors create metastasis-permissive sites to close the door on those sites."

Thrombospondin-1 itself, however, is too large to serve as a drug, and studies using shortened versions of the protein have not been promising. Watnick and his collaborators instead are focusing on prosaposin. To find the smallest part of prosaposin capable of activating thrombospondin-1, the team took an 80-amino acid region of prosaposin and whittled it down bit by bit until they isolated a five amino-acid peptide that could trigger thrombospondin-1 production as strongly as the full-length protein.

When administered in mouse models of metastatic cancer, this peptide significantly reduced metastasis compared to scrambled versions of the peptide (with the same amino acids but in different sequence), but only in mice with monocytes capable of producing thrombospondin-1.

Strikingly, Watnick and his collaborators also found that prostate cancer patients whose tumors expressed higher levels of prosaposin had significantly greater overall survival than patients whose tumors expressed low levels of prosaposin. Thus, with additional work, Watnick believes the prosaposin peptide could be the foundation for a tumor- and location-agnostic method of treating or preventing metastasis in patients with advanced cancers.

"The size of this peptide makes it ideal for drug development," Watnick says. "It's about as large as tyrosine kinase inhibitors such as Gleevec or Iressa, and could potentially be formulated in multiple ways for different types of cancer. I could also foresee using a therapeutic agent like this peptide as an adjuvant therapy, for example just as we now use chemotherapy or hormonal therapy for breast cancer."

Boston Children's Technology and Innovation Development Office (TIDO) has filed patent applications on these peptides, peptide derivatives and their uses. A start-up company is in the works.

The study was supported by the National Cancer Institute (grants R01CA135417 and U54CA143876), the Norwegian Cancer Society, the Norwegian Research Council, the Robert I. Goldman Foundation, the Elsa U. Pardee Foundation, the Boston Children's Hospital Technology Development Fund, the Government of Navarra, Spain, and the Navarra Chamber of Commerce.

Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and 11 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children's also is a teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org/.

Keri Stedman | EurekAlert!
Further information:
http://vectorblog.org
http://www.childrenshospital.org

More articles from Health and Medicine:

nachricht Collagen nanofibrils in mammalian tissues get stronger with exercise
14.12.2018 | University of Illinois College of Engineering

nachricht New discoveries predict ability to forecast dementia from single molecule
12.12.2018 | UT Southwestern Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Data use draining your battery? Tiny device to speed up memory while also saving power

14.12.2018 | Power and Electrical Engineering

Tangled magnetic fields power cosmic particle accelerators

14.12.2018 | Physics and Astronomy

In search of missing worlds, Hubble finds a fast evaporating exoplanet

14.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>