Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway.
Metastases from prostatic adenocarcinoma (prostate cancer) are characterized by their predilection for bone and typical osteoblastic features. An in vitro model of bone metastases from prostate cancer was developed using a bicompartment coculture system of mouse osteoblasts and human prostate cancer cells. In this model, the bone-derived prostate cancer cell lines MDA PCa 2a and MDA PCa 2b induced a specific and reproducible increase in osteoblast proliferation. Moreover, these cells were able to induce osteoblast differentiation, as assessed by increased alkaline phosphatase activity, Osteocalcin expression, and calcified matrix formation. This osteoblastic reaction was confirmed in vivo by intrafemoral injection of MDA PCa 2b cells into severe combined immunodeficiency disease mice. In contrast, the highly undifferentiated, bone-derived human prostate cancer cell line PC3 did not produce an osteoblastic reaction in vitro and induced osteolytic lesions in vivo. The osteoblast differentiation induced by MDA PCa 2b cells was associated with up-regulation of the osteoblast-specific transcriptor factor Cbfa1. Moreover, treatment of osteoblasts with conditioned medium obtained from MDA PCa 2b cells resulted in up-regulation of Cbfa1 and Osteocalcin expression. In support of the differentiation studies, a microarray analysis showed that primary mouse osteoblasts grown in the presence of MDA PCa 2b cells showed a shift in the pattern of gene expression with an increase in mRNA-encoding Procollagen type I and Osteopontin and a decrease in mRNA-encoding proteins associated with myoblast differentiation, namely myoglobin and myosin light-chain 2. Taken together, these findings suggest that the bone-derived prostate cancer cells MDA PCa 2a and MDA PCa 2b promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-dependent pathway. These results also established that soluble factors produced by prostate cancer cells can induce expression of osteoblast-specific genes. This in vitro model provides a valuable system to isolate molecules secreted by prostate cancer cells that favor osteoblast differentiation. Moreover, it allows to screen for therapeutic agents blocking the osteoblast response to prostate cancer.
Yang
J
J
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Fizazi
K
K
Peleg
S
S
Sikes
C R
CR
Raymond
A K
AK
Jamal
N
N
Hu
M
M
Olive
M
M
Martinez
L A
LA
Wood
C G
CG
Logothetis
C J
CJ
Karsenty
G
G
Navone
N M
NM
D000818:Animals; D015152:Blotting, Northern; D001842:Bone and Bones / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned; D009363:Neoplasm Proteins; D014157:Transcription Factors; D015675:Osteocalcin; D012313:RNA; D017430:Prostate-Specific Antigen