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 metastasisprone organs. Osteosarcoma is a malignant tumor of bone made devastating through aggressive metastatic spread primarily to the lung. Mechanisms driving this tropism for lung tissue remain elusive though likely invoke specific interactions between tumor cells and the

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... microenvironment. Methods: By using spontaneous metastatic models, we investigated whether lung epithelial cells are essential for primary tumor induced neutrophil recruitment in lung and subsequently initiating PMN formation in osteosarcoma. Effects of a non-RGD-based integrin binding peptide (ATN-161) on osteosarcoma metastasis was examined in tail-vein mouse injection model. Results: Serum levels of ANGPTL2 in osteosarcoma patients are significantly higher compared to those in healthy controls. Tumor-derived ANGPTL2 stimulates lung epithelial cells, which is essential for primary tumor-induced neutrophil recruitment in lung and subsequent pre-metastatic niche formation. In addition, tumor cell-derived ANGPTL2 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the transendothelial passage of tumor cells. Furthermore, we showed that pharmaceutical inhibition of ANGPTL2 signaling by ATN-161 diminished metastatic load in lungs likely due to reduction of the lung pre-metastatic niche formation. Conclusions: Our data provide plausible evidence that activation of lung epithelial α5β1 receptor by ANGPTL2 induces chemokine production and neutrophil recruitment causing tumor growth-favoring lung microenvironment for incoming metastatic cancer cells. Pharmaceutical inhibition of ANGPTL2 signaling by ATN-161 diminished metastatic load suggesting possible therapeutic utility of ATN-161 in early stage osteosarcoma in children.