title: Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1.
abstract: 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.
  
  
  CONCLUSIONS
  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: Department of Cardiothoracic Surgery, College of Cornell University, New York, NY, USA.
authors: Raúl
authors: R
authors: Catena
authors: Nandita
authors: N
authors: Bhattacharya
authors: Tina
authors: T
authors: El Rayes
authors: Suming
authors: S
authors: Wang
authors: Hyejin
authors: H
authors: Choi
authors: Dingcheng
authors: D
authors: Gao
authors: Seongho
authors: S
authors: Ryu
authors: Natasha
authors: N
authors: Joshi
authors: Diane
authors: D
authors: Bielenberg
authors: Sharrell B
authors: SB
authors: Lee
authors: Svein A
authors: SA
authors: Haukaas
authors: Karsten
authors: K
authors: Gravdal
authors: Ole J
authors: OJ
authors: Halvorsen
authors: Lars A
authors: LA
authors: Akslen
authors: Randolph S
authors: RS
authors: Watnick
authors: Vivek
authors: V
authors: Mittal
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C509295:ITGAM protein, human; D009842:Oligopeptides; D019700:Thrombospondin 1
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