Tumor secreted ANGPTL2 facilitates recruitment of neutrophils to the lung to promote lung pre-metastatic niche formation and targeting ANGPTL2 signaling affects metastatic disease
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// Manish Charan 1 , Piyush Dravid 1 , Maren Cam 1 , Bhuvana Setty 2 , 4 , Ryan D. Roberts 1 , 4 , Peter J. Houghton 3 and Hakan Cam 1 , 4 1 Center for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, Columbus, Ohio, USA 2 Department of Hematology & Oncology, Nationwide Children’s Hospital, Columbus, Ohio, USA 3 Greehey Children’s Cancer Research Institute, Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 4 Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA Correspondence to: Hakan Cam, email: hcam@cscc.edu Keywords: pre-metastatic niche formation; osteosarcoma; ANGPTL2; tumor microenvironment; neutrophils Received: October 22, 2019 Accepted: December 28, 2019 Published: February 04, 2020 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.
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ANGPTL2 and the RANK-RANKL-OPG system have been identified as key contributors to formation of the pre-metastatic niche in the lung in osteosarcoma.
“Similarly, ANGPTL2 77 and the RANK-RANKL-OPG system 78 have been identified as key contributors to the formation of the pre-metastatic niche in the lung.”
From Osteosarcoma (2022) · cites this paper as [77]
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- Authors
- Charan, M., Dravid, P., Cam, M., Setty, B., Roberts, R. D., Houghton, P. J., & Cam, H.
- Affiliations
- Nationwide Children's Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- Center for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Corresponding author
- Cam, Maren
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2020-02-04
- Volume
- 11
- Issue
- 5
- Pages
- 510-522
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC7007290
- OpenAlex
- W3005312454
- Cited by
- 41
- References
- 45
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 5
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Nationwide Children's Hospital (K08CA201638)
- CancerFree KIDS
- National Institutes of Health (UL1TR001070)
- National Cancer Institute (P01CA165995, K08CA201638)
- National Center for Advancing Translational Sciences
- Hyundai Hope On Wheels
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- ANGPTL2, pre-metastatic niche, osteosarcoma, lung metastasis, neutrophil recruitment, lung epithelial cells, tumor microenvironment, ΔNp63, integrin-binding peptides, tumor-secreted factors
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