Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1.
Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1.
复制标题
DOI：
10.1158/2159-8290.cd-12-0476
复制
发表时间：
2013-05
期刊：
影响因子：
28.2
通讯作者：
Mittal V
中科院分区：
文献类型：
--
作者：
Catena R;Bhattacharya N;El Rayes T;Wang S;Choi H;Gao D;Ryu S;Joshi N;Bielenberg D;Lee SB;Haukaas SA;Gravdal K;Halvorsen OJ;Akslen LA;Watnick RS;Mittal V
转移性肿瘤已显示通过募集骨髓（BM）来源的细胞来建立允许转移的微环境。在这里，我们表明，无转移能力的肿瘤也能够产生这样的微环境。然而，在这些情况下，否则促转移Gr 1+骨髓细胞通过肿瘤分泌的鞘脂激活蛋白原诱导血小板反应蛋白-1（Tsp-1）而产生转移难治性微环境。Tsp-1的BM特异性基因缺失消除了对转移的抑制，这通过来自Tsp-1+供体的BM移植而恢复。我们还开发了一种来自saposin原的5-氨基酸肽作为Gr 1 + BM细胞中Tsp-1的药理学诱导剂，其显著抑制转移。这些结果为为什么某些肿瘤缺乏转移潜力提供了机制性见解，并涉及招募的Gr 1+骨髓细胞作为Tsp-1的主要来源。结果强调了Gr 1+细胞的可塑性，根据上下文，促进或抑制转移，并表明该肽可能是一种潜在的治疗药物，用于治疗转移性癌症。
Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow (BM)- derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations the otherwise pro-metastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. (BM)-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by BM transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacological inducer of Tsp-1 in Gr1+ BM cells, which dramatically suppresses 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.