Prostate cancer cells regulate growth and differentiation of bone marrow endothelial cells through TGFβ and its receptor, TGFβRII

• Published in: The Prostate 2006-05, Vol.66 (6), p.632-650
• Main Authors: Barrett, Jeffrey M., Rovedo, Mark A., Tajuddin, Aamair M., Jilling, Tamas, Macoska, Jill A., MacDonald, James, Mangold, Kathy A., Kaul, Karen L.
• Format: Article
• Language: English
• Subjects: angiogenesis; Biological and medical sciences; bone metastasis; endothelium; Gynecology. Andrology. Obstetrics; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; prostate cancer; TGFβ; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20370

BACKGROUND The underlying mechanisms permitting prostate cancer bone metastasis are poorly understood. We previously showed that the highly metastatic prostate cancer cell line, PC‐3, inhibits bone marrow endothelial (HBME‐1) cell growth in collagen gels and induces them to differentiate into cords, resembling angiogenesis in vivo. METHODS cDNA microarray analysis was performed to identify cytokines responsible for the effects of PC‐3 cells on HBME‐1 cells. Cytokine and neutralizing antibody studies were done to further investigate specific angiogenic factors, such as transforming growth factor β (TGFβ). TGFβ RNA and protein were detected by real‐time RT‐PCR and enzyme‐linked immunosorbent assay (ELISA) analysis to measure their production by prostate cancer cell lines. Conditioned media experiments using TGFβ neutralizing antibodies were used to analyze TGFβ activation by prostate cancer cells. RESULTS PC‐3 conditioned media altered the expression of several TGFβ‐regulated or ‐associated genes in HBME‐1 cells. Low concentrations of TGFβ cytokines inhibited HBME‐1 cell growth to a similar level as PC‐3 conditioned media and partially induced differentiation. Inhibitors and neutralizing antibodies directed against TGFβ isoforms and TGFβ receptor type 2 (TGFβRII) reversed the growth inhibition of HBME‐1 cells conferred by PC‐3 conditioned media. Yet, only TGFβRII neutralizing antibodies significantly inhibited HBME‐1 differentiation. Also, prostate cancer cell lines produced low levels of TGFβ RNA and protein, and were shown to activate serum‐derived TGFβ. CONCLUSIONS These results suggest that prostate cancer cells mediate growth inhibition and differentiation of bone marrow endothelial cells both through production and activation of TGFβ as well as alteration of TGFβRII‐mediated signal transduction. This could contribute to the establishment and growth of bone metastases. Prostate 66:632–650, 2006. © 2005 Wiley‐Liss, Inc.