Abstract | UNLABELLED: 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.
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Authors | Raúl Catena, Nandita Bhattacharya, Tina El Rayes, Suming Wang, Hyejin Choi, Dingcheng Gao, Seongho Ryu, Natasha Joshi, Diane Bielenberg, Sharrell B Lee, Svein A Haukaas, Karsten Gravdal, Ole J Halvorsen, Lars A Akslen, Randolph S Watnick, Vivek Mittal |
Journal | Cancer discovery
(Cancer Discov)
Vol. 3
Issue 5
Pg. 578-89
(May 2013)
ISSN: 2159-8290 [Electronic] United States |
PMID | 23633432
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, Ly
- CD11b Antigen
- ITGAM protein, human
- Oligopeptides
- Thrombospondin 1
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Topics |
- Animals
- Antigens, Ly
(metabolism)
- Bone Marrow Cells
(cytology)
- CD11b Antigen
(metabolism)
- Cell Line, Tumor
- Female
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neoplasm Metastasis
- Neoplasms
(metabolism)
- Oligopeptides
(pharmacology)
- Thrombospondin 1
(metabolism)
- Tumor Microenvironment
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