Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING LLC
PZ HTL SA
GLOBETECH PUBLISHING LLC

Nonmetastatic Tumors Release Proteins That Condition the Body Against Cancer Spread

By BiotechDaily International staff writers
Posted on 04 Jun 2013
Image: Contributing author Dr. Randolph Watnick (Photo courtesy of Harvard Medical School).
Image: Contributing author Dr. Randolph Watnick (Photo courtesy of Harvard Medical School).
Cancer researchers have found that certain cancers that do not metastasize, produce and secrete the protein thrombospondin-1 (Tsp-1) and, by doing so, condition distant organs to suppress metastasis.

Tsp-1 is a member of the thrombospondin family of multidomain matrix glycoproteins and has been shown to be a natural inhibitor of neovascularization and tumorigenesis in healthy tissue. Tsp-1 interacts with at least 12 cell adhesion receptors, including CD36, alpha-v and beta-1 integrins, syndecan, and integrin-associated protein (IAP or CD47). It also interacts with numerous proteases involved in angiogenesis, including plasminogen, urokinase, matrix metalloproteinase, thrombin, cathepsin, and elastase.

Investigators at the Harvard Medical School (Boston, MA, USA) had previously shown that tumors that did not metastasize released the protein prosaposin. This protein in turn activated the potent antiangiogenic expression of Tsp-1. Prosaposin is a precursor for four cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator PrO[S]teINs. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins localize primarily to the lysosomal compartment of cells where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups.

In the current study, the investigators performed bone marrow transplant and gene knockout experiments on mouse models of metastatic and nonmetastatic prostate, breast, and lung tumors.

They reported in the May 2013 issue of the journal Cancer Discovery that both types of tumor induced cells from bone marrow monocytes expressing the Gr1 surface marker to migrate to the lungs. However, nonmetastatic tumors produced and secreted the protein prosaposin, which induced production of Tsp-1 by these monocytes. A review of the clinical literature revealed 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.

Genetic deletion of Tsp-1 from the bone marrow abolished the inhibition of metastasis, which could then be restored by bone marrow transplant from Tsp-1-positive donors.

"In the past, we have struggled to determine the source of thrombospondin-1 production," said contributing author Dr. Randolph Watnick, assistant professor of surgery at Harvard Medical School. "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. Others have shown that tumors recruit monocytes to future metastatic sites, which help to set up a permissive environment for tumor cells to metastasize. Our results suggest that nonmetastatic tumors do the same thing, but instead of creating a permissive environment, the monocytes create a refractory environment by producing thrombospondin-1."

The investigators described the development of a five-amino acid peptide from prosaposin that was able to induce Tsp-1 expression in Gr1-positive bone marrow cells, which dramatically suppressed metastasis.

"The size of this peptide makes it ideal for drug development," said Dr. Watnick. "It is 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."

Related Links:

Harvard Medical School



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: The nano-cocoon drug delivery system is biocompatible, specifically targets cancer cells, can carry a large drug load, and releases the drugs very quickly once inside the cancer cell. Ligands on the surface of the \"cocoon\" trick cancer cells into consuming it. Enzymes (the “worms\" in this image) inside the cocoon are unleashed once inside the cell, destroying the cocoon and releasing anticancer drugs into the cell (Photo courtesy of Dr. Zhen Gu, North Carolina State University).

Novel Anticancer Drug Delivery System Utilizes DNA-Based Nanocapsules

A novel DNA-based drug delivery system minimizes damage to normal tissues by utilizing the acidic microenvironment inside cancer cells to trigger the directed release of the anticancer drug doxorubicin (DOX).... Read more

Lab Technologies

view channel

Experimental Physicists Find Clues into How Radiotherapy Kills Cancer Cells

A new discovery in experimental physics has implications for a better determination of the process in which radiotherapy destroys cancer cells. Dr. Jason Greenwood from Queen’s University Belfast (Ireland) Center for Plasma Physics collaborated with scientists from Italy and Spain on the work on electrons, and published... Read more

Business

view channel

Interest in Commercial Applications for Proteomics Continues to Grow

Increasing interest in the field of proteomics has led to a series of agreements between private proteomic companies and academic institutions as well as deals between pharmaceutical companies and novel proteomics innovator biotech companies. Proteomics is the study of the structure and function of proteins.... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.