Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/92506
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Podocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy
Author: Snyder, K.
Hughes, M.
Hedberg, B.
Brandon, J.
Hernaez, D.
Bergqvist, P.
Cruz, F.
Po, K.
Graves, M.
Turvey, M.
Nielsen, J.
Wilkins, J.
McColl, S.
Babcook, J.
Roskelley, C.
McNagny, K.
Citation: Breast Cancer Research, 2015; 17(1):46-1-46-46
Publisher: BioMed Central
Issue Date: 2015
ISSN: 1465-5411
1465-542X
Statement of
Responsibility: 
Kimberly A Snyder, Michael R Hughes, Bradley Hedberg, Jill Brandon, Diana Canals Hernaez, Peter Bergqvist, Frederic Cruz, Kelvin Po, Marcia L Graves, Michelle E Turvey, Julie S Nielsen, John A Wilkins, Shaun R McColl, John S Babcook, Calvin D Roskelley, and Kelly M McNagny
Abstract: INTRODUCTION: Podocalyxin (gene name PODXL) is a CD34-related sialomucin implicated in the regulation of cell adhesion, migration and polarity. Upregulated expression of podocalyxin is linked to poor patient survival in epithelial cancers. However, it is not known if podocalyxin has a functional role in tumor progression. METHODS: We silenced podocalyxin expression in the aggressive basal-like human (MDA-MB-231) and mouse (4T1) breast cancer cell lines and also overexpressed podocalyxin in the more benign human breast cancer cell line, MCF7. We evaluated how podocalyxin affects tumorsphere formation in vitro and compared the ability of podocalyxin-deficient and podocalyxin-replete cell lines to form tumors and metastasize using xenogenic or syngeneic transplant models in mice. Finally, in an effort to develop therapeutic treatments for systemic cancers, we generated a series of antihuman podocalyxin antibodies and screened these for their ability to inhibit tumor progression in xenografted mice. RESULTS: Although deletion of podocalyxin does not alter gross cell morphology and growth under standard (adherent) culture conditions, expression of PODXL is required for efficient formation of tumorspheres in vitro. Correspondingly, silencing podocalyxin resulted in attenuated primary tumor growth and invasiveness in mice and severely impaired the formation of distant metastases. Likewise, in competitive tumor engraftment assays where we injected a 50:50 mixture of control and shPODXL (short-hairpin RNA targeting PODXL)-expressing cells, we found that podocalyxin-deficient cells exhibited a striking decrease in the ability to form clonal tumors in the lung, liver and bone marrow. Finally, to validate podocalyxin as a viable target for immunotherapy, we screened a series of novel antihuman podocalyxin antibodies for their ability to inhibit tumor progression in vivo. One of these antibodies, PODOC1, potently blocked tumor growth and metastasis. CONCLUSIONS: We show that podocalyxin plays a key role in the formation of primary tumors and distant tumor metastasis. In addition, we validate podocalyxin as potential target for monoclonal antibody therapy to inhibit primary tumor growth and systemic dissemination.
Keywords: Cell Line, Tumor
Spheroids, Cellular
Tumor Cells, Cultured
Animals
Humans
Mice
Breast Neoplasms
Mammary Neoplasms, Animal
Cell Transformation, Neoplastic
Neoplasm Metastasis
Disease Models, Animal
Sialoglycoproteins
RNA, Small Interfering
Antineoplastic Agents
Antibodies, Monoclonal
Tumor Burden
Xenograft Model Antitumor Assays
RNA Interference
Female
Rights: © 2015 Snyder et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
DOI: 10.1186/s13058-015-0562-7
Grant ID: NHMRC
Appears in Collections:Aurora harvest 2
IPAS publications

Files in This Item:
File Description SizeFormat 
hdl_92506.pdfPublished version3.03 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.