Tumor secreted ANGPTL2 facilitates recruitment of neutrophils to the lung to promote lung pre-metastatic niche formation and targeting ANGPTL2 signaling affects metastatic disease

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 metastasisprone 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.

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

“…Additionally, tumor-infiltrating myeloid cells were documented to be critical drivers of radiation-induced osteosarcomagenesis in mice [ 38 ]. Osteosarcoma-secreted angiopoietin like 2 (ANGPTL2) was recently demonstrated to recruit neutrophils in pre-metastatic lungs, and Ly6G mediated depletion of these neutrophils resulted in decreased spontaneous metastasis in syngeneic osteosarcoma models [ 39 ]. Anti-tumorigenic effects have also been reported where the type 2 diabetes drug, metformin was shown to induce anti-tumor effects through the metabolic reprogramming of CD11b + myeloid cells, causing them to inhibit osteosarcoma tumor growth [ 40 ].…”

“…Additionally, high VEGF and TGFβ expression have been associated with a poor prognosis among patients with osteosarcoma [ 41 , 42 ], and interruption of VEGF and TGFβ signaling was shown to disrupt osteosarcoma progression and metastasis [ 42 , 43 ]. Other soluble factors, such as IL-8 and ANGPTL2 have been additionally shown to mediate osteosarcoma metastatic progression and PMN formation in different mouse models [ 39 , 44 ]. These reports collectively provide evidence that tumor-secreted factors are also involved in osteosarcoma PMN formation, but further investigation is still required to help understand if they act in combination with EVs to establish a functional PMN.…”

Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer

“…Immunoblotting was performed as described in ref. 15 . Briefly, cell lysates were separated on NuPAGE 4-12% gradient precast gels (Invitrogen), transferred onto 0.45 μm nitrocellulose membranes (BioRad), and probed with the appropriate dilution of specific primary antibodies (Supplementary Table 3).…”

Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche

“…Monocytes, neutrophils, and macrophages are the main components of the microenvironment of metastatic tumors, affecting the recruitment and extravasation of tumor cells before metastasis. ANGPTL2 initiates programs that lead to neutrophil recruitment within the lung, a process essential for the lung colonization in spontaneous models of osteosarcoma pulmonary metastasis [22]. Hyunho Kim et al developed a microfluidic platform that incorporates endothelial cells and extracellular matrix scaffolds, proved monocyte-derived matrix metalloproteinase 9 facilitates cancer cell extravasation through destruction of endothelial tight junctions, and macrophages could reduced migratory capacity of cancer cells [23].…”