Journal
CANCER DISCOVERY
Volume 3, Issue 5, Pages 578-589Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0476
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Funding
- NIH [CA135417]
- Norwegian Cancer Society
- Norwegian Research Council
- Cornell Center on the Microenvironment and Metastasis from the NCI [U54CA143876]
- Robert I. Goldman Foundation
- Elsa U. Pardee Foundation
- Boston Children's Hospital Technology Development Grant
- Government of Navarra
- Camara Navarra de Comercio (Navarra, Spain)
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Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1(+) myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1(+) donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1(+) bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1(+) myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1(+) cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. SIGNIFICANCE: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow-derived Gr1(+) myeloid cells. A 5-amino acid peptide with Tsp-1-inducing activity was identified as a therapeutic agent against metastatic cancer. Cancer Discov; 3(5); 578-89. (C) 2013 AACR.
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