Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions.
BACKGROUND
Although a majority of metastatic prostate cancer lesions are osteoblastic in nature, some are mixed or lytic; and, osteoblastic lesions require osteolytic activity in order to progress. The role of BMPs in the formation of prostate cancer metastases to bone remains unknown. We hypothesized that BMPs influence the development and progression of osteolytic prostate cancer lesions.


METHODS
RT-PCR and Western blot analysis were used to determine BMP receptor expression on the osteolytic prostate cancer cell line PC-3. Migration, invasion, and cellular proliferation assays were performed on PC-3 cells to quantify the effects of BMP-2, -4, and -7. In vivo, PC-3 cells were injected alone, with an empty retroviral vector, or with a retroviral vector overexpressing noggin, into the tibias of SCID mice. The animals were followed for 8 weeks, and histologic and radiographic analysis were performed at 2, 4, 6, and 8 weeks.


RESULTS
BMP receptors are expressed on PC-3 cells, suggesting that they would be responsive to host BMP secretion. BMP-2, and to a lesser extent, BMP-4, stimulated PC-3 cell migration and invasion in a dose-dependent fashion. Noggin inhibited cellular migration and invasion of BMP-2 and -4 stimulated PC-3 cells. BMP-2 alone stimulated PC-3 cell proliferation, but BMP-4 had no effect. BMP-7 had no effect on proliferation, migration, or invasion. PC-3 cells implanted into SCID mouse tibias formed osteolytic lesions as early as 2 weeks and completely destroyed the proximal tibia by 8 weeks. Overexpression of noggin in PC-3 cells inhibited the expansion of the lesion in vivo.


CONCLUSIONS
BMPs influence the formation of the osteolytic prostate cancer metastases, and treatment modalities that inhibit BMP activity may limit the progression of the lytic component of prostate cancer metastases.
Feeley
Brian T
BT
Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences 76-134, 10833 LeConte Avenue, Los Angeles, CA 90095, USA. bfeeley@mednet.ucla.edu
Krenek
Lucie
L
Liu
Nancy
N
Hsu
Wellington K
WK
Gamradt
Seth C
SC
Schwarz
Edward M
EM
Huard
Johnny
J
Lieberman
Jay R
JR
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000556:secondary; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525819:BMP7 protein, human; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; C525821:Bmp7 protein, rat