Charan Manish, Dravid Piyush, Cam Maren, Setty Bhuvana, Roberts Ryan D, Houghton Peter J, Cam Hakan
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio, USA.
Department of Hematology & Oncology, Nationwide Children's Hospital, Columbus, Ohio, USA.
Oncotarget. 2020 Feb 4;11(5):510-522. doi: 10.18632/oncotarget.27433.
The pre-metastatic niche (PMN) represents an abnormal microenvironment devoid of cancer cells, but favoring tumor growth. Little is known about the mechanisms that generate the PMN or their effects on host cells within metastasis-prone organs. Here, we investigated by using spontaneous metastatic models whether lung epithelial cells are essential for primary tumor induced neutrophil recruitment in lung and subsequently initiating PMN formation in osteosarcoma. We found that serum levels of ANGPTL2 in osteosarcoma patients are significantly higher compared to those in healthy controls and that ANGPTL2 secretion by tumor cells plays an essential role in osteosarcoma metastasis. We determined that tumor-derived ANGPTL2 stimulates lung epithelial cells, which is essential for primary tumor-induced neutrophil recruitment in lung and subsequent pre-metastatic niche formation. Lastly, we identified that a p63 isoform, ΔNp63, drives high level of ANGPTL2 secretion and pharmaceutical inhibition of ANGPTL2 signaling by a non-RGD-based integrin binding peptide (ATN-161) diminished metastatic load in lungs likely due to reduction of the lung pre-metastatic niche formation.
前转移微环境（PMN）是一种不存在癌细胞但有利于肿瘤生长的异常微环境。对于产生PMN的机制或其对易发生转移器官内宿主细胞的影响，人们了解甚少。在这里，我们通过使用自发转移模型研究肺上皮细胞对于原发性肿瘤诱导肺内中性粒细胞募集以及随后启动骨肉瘤中PMN形成是否至关重要。我们发现，与健康对照相比，骨肉瘤患者血清中血管生成素样蛋白2（ANGPTL2）水平显著更高，并且肿瘤细胞分泌的ANGPTL2在骨肉瘤转移中起重要作用。我们确定肿瘤来源的ANGPTL2刺激肺上皮细胞，这对于原发性肿瘤诱导肺内中性粒细胞募集以及随后的前转移微环境形成至关重要。最后，我们发现一种p63异构体ΔNp63驱动高水平的ANGPTL2分泌，并且基于非RGD的整合素结合肽（ATN-161）对ANGPTL2信号的药物抑制可能由于肺前转移微环境形成的减少而降低了肺内的转移负荷。
