Osteoblast conditioned media contain TGF-beta1 and modulate the migration of prostate tumor cells and their interactions with extracellular matrix components.
Prostate cancers (PRCAs) frequently metastasize to bone. We show here that this process is facilitated by osteoblast-mediated tumor cell recruitment. Transforming growth factor-beta1 (TGF-beta1) is produced by osteoblasts in a latent form and is activated by proteases in a cell-dependent manner. This cytokine exhibits pleiotropic effects on cell-extracellular matrix (ECM) interactions and may influence tumor cell invasion and metastasis. Our purpose was to identify the potential molecular mechanisms involved in osteoblast-mediated cell recruitment and to characterize the effect of TGF-beta1 on adhesion, motility and invasiveness of a human prostate cancer cell line with high bone metastatic potential (PC3 cell line) in vitro. Conditioned media from osteoblast cultures (OB CM) enhanced PC3 cell chemotaxis and invasion of reconstituted basement membrane. These effects were blocked by a neutralizing TGF-beta1 polyclonal antibody but not by elution of the OB CM in agarose-heparin columns, suggesting that TGF-beta1, but not EGF-like proteins, contribute to PC3 cell recruitment. In addition, TGF-beta1 directly induced chemotaxis and invasion of PC3 cells in a dose-dependent manner. The TGF-beta1-mediated invasion and motility were accompanied by increased PC3 cell adhesion, spreading and alpha2beta1 and alpha3beta1 integrin expression. These events are involved in the cell adhesion to several components of basement membrane and ECM and in the selective invasion of metastatic tumor cells. Our results suggest that TGF-beta1 can influence cellular recognition of ECM components by prostatic cancer cells and can modulate cell adhesion and invasion leading to increased invasive potential. Given the widespread tissue distribution of TGF-beta1, and the high levels present in the bone, this cytokine may be an important autocrine-paracrine modulator of the bone invasive phenotype in vivo.
Festuccia
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Department of Experimental Medicine, Medical School, University of L'Aquila, Italy. festucci@univaq.it
Bologna
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Gravina
G L
GL
Guerra
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F
Angelucci
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Villanova
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I
Millimaggi
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D
Teti
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A
D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002633:Chemotaxis; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000032:analysis; D008297:Male; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000502:physiology*
D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D016023:Integrins; D016212:Transforming Growth Factor beta