Bone marrow stromal cells enhance prostate cancer cell invasion through type I collagen in an MMP-12 dependent manner.
At the cellular level, the process of bone metastasis involves many steps. Circulating cancer cells enter the marrow, proliferate, induce neovascularization, and ultimately expand into a clinically detectable, often symptomatic, metastatic deposit. Although the initial establishment and later expansion of the metastatic deposit in bone require tumor cells to possess invasive capability, the exact proteases responsible for this phenotype are not well known. The objective of our study was to take an unbiased approach to determine which proteases were expressed and functional during the initial interactions between prostate cancer cells and bone marrow stromal (BMS) cells. We found that the combination of human prostate cancer PC3 and BMS cells stimulates the invasive ability of cancer cells through type I collagen. The use of inhibitors for each of the major protease families indicated that 1 or more MMPs was/were responsible for the BMS-induced invasion. Gene profiling and semiquantitative RT-PCR analysis revealed an increased expression of several MMP genes because of PC3/BMS cell interaction. However, only MMP-12 showed an increase in protein expression. Downregulation of MMP-12 expression in PC3 cells by siRNA inhibited the enhanced invasion induced by PC3/BMS cell interaction. In vivo, MMP-12 was found to be primarily expressed by prostate cancer cells growing in bone. Our data suggest that BMS cells induce MMP-12 expression in prostate cancer cells, which results in invasive cells capable of degradation of type I collagen.
Nabha
Sanaa M
SM
Department of Urology, Wayne State University School of Medicine and The Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
dos Santos
Emanuel Burck
EB
Yamamoto
Hamilto A
HA
Belizi
Abdelfettah
A
Dong
Zhong
Z
Meng
Hong
H
Saliganan
Allen
A
Sabbota
Aaron
A
Bonfil
R Daniel
RD
Cher
Michael L
ML
D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000473:pathology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D024042:Collagen Type I / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000473:pathology*; D014162:Transfection; D015854:Up-Regulation
D024042:Collagen Type I; D034741:RNA, Small Interfering; D007633:Keratins; D020782:Matrix Metalloproteinases; D053508:Matrix Metalloproteinase 12