A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression.
The platelet-derived growth factor (PDGF) proteins are potent stimulators of cell proliferation/transformation and play a major role in cell-cell communication. For over two decades, PDGFs were thought to exist as three dimeric polypeptides (the homodimers AA and BB and the heterodimer AB). Recently, however, the PDGF C and D chains were discovered in a BLAST search of the expressed sequence tag databases. The PDGF CC and DD dimers have a unique two-domain structure with an NH(2)-terminal CUB (compliment subcomponents C1r/C1s, Uegf, and Bmp1) domain and a COOH-terminal PDGF/vascular endothelial growth factor domain. Whereas secreted PDGF AA, BB, and AB readily activate their cell surface receptors, it was suggested that extracellular proteolytic removal of the CUB domain is required for the PDGF/vascular endothelial growth factor domain of PDGF CC and DD to activate PDGF receptors. In the present study, we examined the processing of latent PDGF D into its active form and the effects of PDGF D expression on prostate cancer progression. We show that LNCaP cells auto-activate latent PDGF DD into the active PDGF domain, which can induce phosphorylation of the beta-PDGF receptor and stimulates LNCaP cell proliferation in an autocrine manner. Additionally, LNCaP-PDGF D-conditioned medium induces migration of the prostate fibroblast cell line 1532-FTX, indicating LNCaP-processed PDGF DD is active in a paracrine manner as well. In a severe combined immunodeficient mouse model, PDGF DD expression accelerates early onset of prostate tumor growth and drastically enhances prostate carcinoma cell interaction with surrounding stromal cells. These demonstrate a potential oncogenic activity of PDGF DD in the development and/or progression of prostate cancer.
Ustach
Carolyn V
CV
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Taube
Marcus E
ME
Hurst
Newton J
NJ
Bhagat
Sunita
S
Bonfil
R Daniel
RD
Cher
Michael L
ML
Schuger
Lucia
L
Kim
Hyeong-Reh Choi
HR
D002450:Cell Communication; D002455:Cell Division; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D008222:Lymphokines; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000209:etiology / Q000473:pathology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D017154:Stromal Cells / Q000502:physiology
D008222:Lymphokines; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta