Stromal factors involved in prostate carcinoma metastasis to bone.
BACKGROUND
Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site.


METHODS
The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth.


RESULTS
The authors demonstrate that PC cells express protease-activated receptor 1 (PAR1; thrombin receptor), and its expression is up-regulated in PC compared with normal prostate tissue. In addition, this overexpression was very pronounced in bone-derived PC cell lines (VCaP and PC-3) compared with soft tissue PC cell lines (DUCaP, DU145, and LNCaP). The authors report that bone stromal factors, including stromal cell-derived factor 1 (SDF-1) and collagen Type I peptides, are chemoattractants for PC cells, and they demonstrate that some of these factors (e.g., extracellular matrix components, transforming growth factor beta, bone morphogenic proteins [BMPs], and SDF-1) significantly alter PC-HBME interaction in vitro. Finally, stromal factors, such as BMPs, can regulate the proliferation of PC cells in vitro.


CONCLUSIONS
Soluble and insoluble elements of the stroma are involved in multiple steps of PC metastasis to bone. The authors hypothesize that PAR1 may play a central role in prostate tumorigenesis.
Cooper
Carlton R
CR
Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0946, USA.
Chay
Christopher H
CH
Gendernalik
James D
JD
Lee
Hyung-Lae
HL
Bhatia
Jasmine
J
Taichman
Russell S
RS
McCauley
Laurie K
LK
Keller
Evan T
ET
Pienta
Kenneth J
KJ
D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D002448:Cell Adhesion; D002450:Cell Communication; D004727:Endothelium / Q000502:physiology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000378:metabolism*; D017154:Stromal Cells / Q000502:physiology*; D015854:Up-Regulation
D019485:Bone Morphogenetic Proteins; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin