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

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.

• 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)

Chemical References

• Antigens, Ly
• CD11b Antigen
• ITGAM protein, human
• Oligopeptides
• Thrombospondin 1

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