Changing cancer's environment to halt its spread

May 21, 2013

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 is not the primary itself, but rather its spread—metastasis—to other locations in the body and subsequent . Previous studies by Watnick, a member of Boston Children's 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 , 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 and gene knockout experiments that both metastatic and non- 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.

Explore further: How some cancers 'poison the soil' to block metastasis

Related Stories

How some cancers 'poison the soil' to block metastasis

April 30, 2013
Cancer spread or metastasis can strike unprecedented fear in the minds of cancer patients. The "seed and the soil" hypothesis proposed by Stephen Paget in 1889 is now widely accepted to explain how cancer cells (seeds) are ...

Researchers discover protein that may control the spread of cancer

February 26, 2013
Researchers at the University of Hawai'i Cancer Center have uncovered a novel mechanism that may lead to more selective ways to stop cancer cells from spreading. Associate Professor Joe W. Ramos PhD, a cancer biologist at ...

Six2 homeoprotein allows breast cancer cells to detach and metastasize

April 9, 2013
In results presented at the AACR Annual Meeting 2013, researchers from the University of Colorado Cancer Center show that the Six2 homeoprotein, while not involved in primary tumor growth, allows cells to detach from substrate ...

MicroRNA molecule may serve as biomarker, target for brain metastases in breast cancer patients

February 5, 2013
Researchers have identified two molecules that could potentially serve as biomarkers in predicting brain metastases in patients with breast cancer, according to data published in Cancer Research, a publication of the American ...

Crucial molecule that involved in spread of breast cancer found

June 8, 2011
Researchers at Albert Einstein College of Medicine of Yeshiva University have identified a key player in the spread of breast cancer. The findings, published today in the online edition of Nature, identify a critical molecule ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.