Abstract
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.
Highlights
Primary tumors selectively and actively modify potential sites of metastasis, even prior to dissemination [1,2,3]
High level of angiopoietin like 2 (ANGPTL2) secretion plays a critical role in osteosarcoma metastasis
We found that ANGPTL2 levels were strikingly elevated in serum from osteosarcoma patients compared to healthy controls (Figure 1A)
Summary
Primary tumors selectively and actively modify potential sites of metastasis, even prior to dissemination [1,2,3]. This “tumor-education” at a distance results when tumor-secreted factors and extracellular vesicles shed by tumor cells elicit changes in distant tissues that facilitate subsequent outgrowth of disseminated cancer cells. Some reports have suggested that lung epithelial cells can respond to tumor-derived signals in ways that trigger pre-metastatic niche formation (reviewed in [1]). We set out to determine how tumor-derived factors might affect the activation of lung epithelial cells in ways that elicit pro-metastatic inflammatory responses and facilitate the formation of the pre-metastatic following recruitment of neutrophils
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