Nonmetastatic Tumors Release Proteins That Condition the Body Against Cancer Spread

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."

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