Regulation of global gene expression in the bone marrow microenvironment by androgen: androgen ablation increases insulin-like growth factor binding protein-5 expression.
BACKGROUND
Prostate cancer frequently metastasizes to bone. Androgen suppression treatment is initially highly effective, but eventually results in resistant cancer cells. This study evaluates the effects of androgen suppression on the bone and bone marrow (BM). In particular we questioned whether the androgen therapy could adversely facilitate prostate cancer progression through an increase growth factor secretion by the bone microenvironment.


METHODS
Global gene expression is analyzed on mPEDB DNA microarrays. Insulin-like growth factor binding protein-5 (IGFBP5) is detected by immunohistochemistry in mouse tissues and its regulation measured by qPCR and Western blotting in human BM stromal cells. Effects of extracellular matrix-associated IGFBP5 on human prostate epithelial cells are tested in an MTS cell-growth assay.


RESULTS
Castration increases expression of 159 genes (including 4 secreted cytokines) and suppresses expression of 84 genes. IGFBP5 is most consistently increased and the increase in expression is reversed by testosterone administration. IGFBP5 protein is detected in vivo in osteoblasts, BM stromal cells, and endothelial cells. Primary human stromal cell cultures secrete IGFBP5. In vitro, treatment of immortalized human marrow stromal cells with charcoal-stripped serum increases IGFBP5 mRNA expression, which is reversed by androgen supplementation. IGFBP5 is incorporated into the extracellular matrix. Further, IGFBP5 immobilized on extracellular matrices of stromal cells enhances the growth of immortalized prostate epithelial cells.


CONCLUSIONS
Androgen suppressive therapy increases IGFBP5 in the BM microenvironment and thereby may facilitate the progression of prostate cancer.
Xu
Chang
C
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Graf
Lynn F
LF
Fazli
Ladan
L
Coleman
Ilsa M
IM
Mauldin
Denise E
DE
Li
Danbin
D
Nelson
Peter S
PS
Gleave
Martin
M
Plymate
Stephen R
SR
Cox
Michael E
ME
Torok-Storb
Beverly J
BJ
Knudsen
Beatrice S
BS
D000728:Androgens / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012669:Seminal Vesicles / Q000187:drug effects / Q000473:pathology; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*