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

نویسندگان

  • 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
چکیده

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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Cells Can Generate a Metastasis-Resistant Microenvironment Via Induced Secretion of Thrombospondin-1

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عنوان ژورنال:
  • Cancer discovery

دوره 3 5  شماره 

صفحات  -

تاریخ انتشار 2013