TY - JOUR
T1 - Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1
AU - Catena, Raúl
AU - Bhattacharya, Nandita
AU - El Rayes, Tina
AU - Wang, Suming
AU - Choi, Hyejin
AU - Gao, Dingcheng
AU - Ryu, Seongho
AU - Joshi, Natasha
AU - Bielenberg, Diane
AU - Lee, Sharrell B.
AU - Haukaas, Svein A.
AU - Gravdal, Karsten
AU - Halvorsen, Ole J.
AU - Akslen, Lars A.
AU - Watnick, Randolph S.
AU - Mittal, Vivek
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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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U2 - 10.1158/2159-8290.CD-12-0476
DO - 10.1158/2159-8290.CD-12-0476
M3 - Article
C2 - 23633432
AN - SCOPUS:84877602573
SN - 2159-8274
VL - 3
SP - 578
EP - 589
JO - Cancer Discovery
JF - Cancer Discovery
IS - 5
ER -