Featured Research

from universities, journals, and other organizations

Changing cancer's environment to halt its spread

Date:
May 21, 2013
Source:
Boston Children's Hospital
Summary:
By studying the roles two proteins, thrombospondin-1 and prosaposin, play in discouraging cancer metastasis, scientists have 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.

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.


Story Source:

The above story is based on materials provided by Boston Children's Hospital. Note: Materials may be edited for content and length.


Journal Reference:

  1. R. Catena, N. Bhattacharya, T. El Rayes, S. Wang, H. Choi, D. Gao, S. Ryu, N. Joshi, D. Bielenberg, S. B. Lee, S. A. Haukaas, K. Gravdal, O. J. Halvorsen, L. A. Akslen, R. S. Watnick, V. Mittal. Bone Marrow-Derived Gr1 Cells Can Generate a Metastasis-Resistant Microenvironment Via Induced Secretion of Thrombospondin-1. Cancer Discovery, 2013; 3 (5): 578 DOI: 10.1158/2159-8290.CD-12-0476

Cite This Page:

Boston Children's Hospital. "Changing cancer's environment to halt its spread." ScienceDaily. ScienceDaily, 21 May 2013. <www.sciencedaily.com/releases/2013/05/130521194223.htm>.
Boston Children's Hospital. (2013, May 21). Changing cancer's environment to halt its spread. ScienceDaily. Retrieved September 17, 2014 from www.sciencedaily.com/releases/2013/05/130521194223.htm
Boston Children's Hospital. "Changing cancer's environment to halt its spread." ScienceDaily. www.sciencedaily.com/releases/2013/05/130521194223.htm (accessed September 17, 2014).

Share This



More Health & Medicine News

Wednesday, September 17, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

President To Send 3,000 Military Personnel To Fight Ebola

President To Send 3,000 Military Personnel To Fight Ebola

Newsy (Sep. 16, 2014) President Obama is expected to send 3,000 troops to West Africa as part of the effort to contain Ebola's spread. Video provided by Newsy
Powered by NewsLook.com
Man Floats for 31 Hours in Gulf Waters

Man Floats for 31 Hours in Gulf Waters

AP (Sep. 16, 2014) A Texas man is lucky to be alive after he and three others floated for more than a day in the Gulf of Mexico when their boat sank during a fishing trip. (Sept. 16) Video provided by AP
Powered by NewsLook.com
Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

AFP (Sep. 16, 2014) Since the arrival of Ebola in Ivory Coast, Ivorians have been abandoning their pets, particularly monkeys, in the fear that they may transmit the virus. Duration: 00:47 Video provided by AFP
Powered by NewsLook.com
Study Links Male-Pattern Baldness To Prostate Cancer

Study Links Male-Pattern Baldness To Prostate Cancer

Newsy (Sep. 16, 2014) New findings suggest men with a certain type of baldness at age 45 are 39 percent more likely to develop aggressive prostate cancer. Video provided by Newsy
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