Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival.
The microenvironment plays a critical role in facilitating cancer progression and metastasis. We previously demonstrated the ability of osteoclasts to support primary myeloma plasma cell (MM PC) growth. Our study on the role of the bone marrow (BM) microenvironment in myeloma, using global gene expression profiling, has identified fibroblast activation protein (FAP) as one of 28 genes significantly overexpressed in cocultured osteoclasts. Because FAP has been previously implicated in tumorigenesis and shown to be selectively expressed by the reactive stroma of epithelial tumours, we focused our study on the role of this serine protease in myeloma. Using quantitative polymerase chain reaction amplification, we demonstrated upregulation of FAP by cocultured osteoclasts and mesenchymal stem cells, and in whole myelomatous human bone in SCID-hu mice. Immunohistochemical analysis of myelomatous bone sections revealed FAP expression by osteoclasts, osteogenic cells, fibrotic stroma and certain adipocytes and vascular endothelial cells. FAP was not expressed in PCs by all these methods. Inhibition of FAP expression with the use of small-interference RNA reduced MM PC survival in cocultures. Our results indicate that FAP is critical for the interaction of MM cells with the BM microenvironment--a potential therapeutic target in myeloma.
Ge
Yun
Y
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Zhan
Fenghuang
F
Barlogie
Bart
B
Epstein
Joshua
J
Shaughnessy
John
J
Yaccoby
Shmuel
S
D017667:Adipocytes / Q000737:chemistry; D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics; D010450:Endopeptidases; D042783:Endothelial Cells / Q000737:chemistry; D004730:Endothelium, Vascular / Q000737:chemistry; D018093:Gelatinases; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000378:metabolism*; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D015854:Up-Regulation; D000099167:Fibroblast Activation Protein Alpha
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D016207:Cytokines; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha