A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer.
We examined the effect of the extracellular bone morphogenetic protein (BMP) 2 and 7, which are up-regulated in the prostate adenocarcinomas of the conditional Pten deletion mouse model, on primary cultures of cancer-associated fibroblasts (CAF) derived from these tumors. In the CAF, we show that BMP2 or BMP7, but not transforming growth factor beta-1, can strikingly stimulate secretion of stromal cell-derived factor-1 (SDF-1), also known as CXCL12. The CAF cells express type I and type II BMP receptors as well as the receptor for SDF-1, CXCR4. SDF-1 activation is associated with BMP-induced Smad phosphorylation, and the stimulatory effect is blocked by BMP antagonist, noggin. The findings that BMP treatment can increase SDF-1 pre-mRNA levels in a time-dependent manner and actinomycin D treatment can abolish stimulatory effect of BMP suggest a transcriptional modulation of SDF-1 by BMP signaling. Using a human microvascular endothelial cell line, we show that SDF-1 present in the conditioned medium from the stimulated CAF can significantly induce tube formation, an effect relating to angiogenic function. Furthermore, we found that BMP2 can also protect the CAF from serum starvation-induced apoptosis independent of SDF-1, implying that BMP may induce other factors to sustain the survival of these cells. In short, this report establishes a novel BMP-SDF-1 axis in the prostate tumor along with a new prosurvival effect of BMP that when considered together with our previously described oncogenic properties of BMP indicate a circuitry for heterotypic cell interactions potentially critical in prostate cancer.
Yang
Shangxin
S
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Pham
Linda K
LK
Liao
Chun-Peng
CP
Frenkel
Baruch
B
Reddi
A Hari
AH
Roy-Burman
Pradip
P
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000737:chemistry; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000099176:Noggin Protein
D000199:Actins; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; D051059:PTEN Phosphohydrolase; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525819:BMP7 protein, human; C525719:Bmp2 protein, mouse; C487757:Pten protein, mouse