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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 6/2011

01-08-2011 | Research Paper

Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions

Authors: Yan Huang, Avis E. Simms, Anna Mazur, Sophie Wang, Noel R. León, Barry Jones, Nazneen Aziz, Thomas Kelly

Published in: Clinical & Experimental Metastasis | Issue 6/2011

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Abstract

Fibroblast activation protein-α (FAP) is a cell surface, serine protease of the post-prolyl peptidase family that is expressed in human breast cancer but not in normal tissues. Previously, we showed that FAP expression increased tumor growth rates in a mouse model of human breast cancer. Here the role of the proteolytic activities of FAP in promoting tumor growth, matrix degradation and invasion was investigated. Mammary fat pads of female SCID mice were inoculated with breast cancer cells that express FAP and the mice treated with normal saline or Val-boroPro (talabostat); Glu-boroPro (PT-630); or 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine (LAF-237) that inhibit prolyl peptidases. Other mice were injected with breast cancer cells expressing a catalytically inactive mutant of FAP and did not receive inhibitor treatment. PT-630 and LAF-237 did not slow growth of tumors produced by any of the three cell lines expressing FAP. Talabostat slightly decreased the growth rates of the FAP-expressing tumors but because PT-630 and LAF-237 did not, the growth retardation was likely not related to the inhibition of FAP or the related post-prolyl peptidase dipeptidyl peptidase IV. Breast cancer cells expressing a catalytically inactive mutant of FAP (FAPS624A) also produced tumors that grew rapidly. In vitro studies revealed that cells expressing wild type FAP or FAPS624A degrade extracellular matrix (ECM) more extensively, accumulate higher levels of matrix metalloproteinase-9 (MMP-9) in conditioned medium, are more invasive in type I collagen gels, and have altered signaling compared to control transfectants that do not express FAP and form slow growing tumors. We conclude that the proteolytic activity of FAP participates in matrix degradation, but other functions of the protein stimulate increased tumor growth.
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Metadata
Title
Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions
Authors
Yan Huang
Avis E. Simms
Anna Mazur
Sophie Wang
Noel R. León
Barry Jones
Nazneen Aziz
Thomas Kelly
Publication date
01-08-2011
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 6/2011
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-011-9392-x

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