Navigation Links
Changing cancer's environment to halt its spread
Date:5/21/2013

Boston, Mass.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 spreadmetastasisto 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 marrowspecifically, monocytes expressing the Gr1 surface markerto 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.


'/>"/>

Contact: Keri Stedman
keri.stedman@childrens.harvard.edu
617-919-3110
Boston Children's Hospital
Source:Eurekalert

Related medicine news :

1. Brain structure helps guide behavior by anticipating changing demands
2. Birds Songs Reflect Changing Weather Patterns: Study
3. Changing epidemiology of rare disease links sinus irrigation with contaminated tap water, 2 deaths
4. Guidelines developed for extremely premature infants at NCH proven to be life-changing
5. Does changing the price of medicine influence consumers perceived health risk?
6. Changing Poses LLC Brings Balance to Chiropractic Treatment Tables, Complimentary Lavender Spray Cleaner with All Wholesale Orders
7. Panel recommends changing name of common disorder in women
8. Atlanta Opthalmologist Interviewed About LASIK Surgery’s Life-Changing Effects
9. Avoiding Hospital Readmissions Boot Camp and Survive and Thrive in the Changing Health Care Environment - ABQAURP's 36th Annual Health Care Quality Conference
10. Changing shape makes chemotherapy drugs better at targeting cancer cells
11. New data show countries around the world grappling with changing health challenges
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/26/2017)... ... 2017 , ... KICKICO , a protocol built on Ethereum for more ... catastrophic issues within funding campaigns. KICKICO developers are testing the platform, which will launch ... raising of funds through the power of many - has been around for about ...
(Date:6/25/2017)... ... ... lyric music video in Final Cut Pro X with ProLyric from Pixel Film Studios. Users ... to any song. ProLyric flies in the text for each section and it hovers around ... for optimal control. ProLyric makes editing any music video or text-based production easier than ever. ...
(Date:6/25/2017)... , ... June 25, 2017 , ... CareSet Labs released ... in New Orleans. This is a new, greatly improved version of the Doctor Referral ... (FOIA) requests by Fred Trotter and subsequently called the the “Doctor Referral Dataset” as ...
(Date:6/24/2017)... ... June 24, 2017 , ... ... testing for medications in select Florida and Texas doctors' offices and clinics. This ... new application of genetic testing recognizes the role genes play in determining an ...
(Date:6/24/2017)... , ... June 24, 2017 , ... The weather is ... time outdoors. Home and business owners should be aware that the summer months provide ... In fact, mechanical locks and keys can be negatively affected from direct exposure to ...
Breaking Medicine News(10 mins):
(Date:6/9/2017)... PALO ALTO, Calif. , June 9, 2017 /PRNewswire/ ... medical device company focused on the design, manufacture, sale ... updated the market on the progress of its commercial ... AeroForm is now available in more than one hundred ... country. AeroForm offers a needle-free alternative ...
(Date:6/8/2017)... 8, 2017   Responding to Heath Ledger,s ... death of singer Chris Cornell in May, the ... offers a free online psychiatric drug side ... families about psychotropic drug risks. The father ... from an accidental overdose, has called for tighter rules on ...
(Date:6/7/2017)... 7, 2017  Novavax, Inc., (Nasdaq: NVAX ) ... 2 trials of its RSV F protein recombinant nanoparticle vaccine ... have been published in the journal Vaccine ... in prior scientific conferences). The Company previously announced top ... is developing the RSV F Vaccine with the goal of ...
Breaking Medicine Technology: