Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1

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

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)578-589
Number of pages12
JournalCancer Discovery
Issue number5
StatePublished - May 2013

ASJC Scopus subject areas

  • Oncology


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