Coculture with Prostate Cancer Cells Alters Endoglin Expression and Attenuates Transforming Growth Factor-β Signaling in Reactive Bone Marrow Stromal Cells

• Published in: Molecular cancer research Vol. 5; no. 6; pp. 585 - 603
• Main Authors: O'Connor, John C., Farach-Carson, Mary C., Schneider, Charles J., Carson, Daniel D.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-06-2007
• Subjects: Antigens, CD - metabolism; Apoptosis; Bone and Bones - metabolism; Bone Marrow Cells - cytology; bone stroma; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Culture Media, Conditioned - pharmacology; Endoglin; Humans; Male; Neoplasm Metastasis; prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Cell Surface - metabolism; Signal Transduction; Smad signaling; Stromal Cells - cytology; TGF-β; Transforming Growth Factor beta - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-06-0408

A dynamic interplay between prostate cancer cells and reactive bone stroma modulates growth of metastases within bone. We
used microarray analysis to screen for changes in gene expression in bone marrow stromal cells cocultured with prostate cancer
cells and found reduced expression of endoglin, a transmembrane glycoprotein that functions as an auxiliary coreceptor for
members of the transforming growth factor β (TGF-β) family of cytokines. The downstream TGF-β/bone morphogenetic protein signaling
pathway including Smad1 and Smad2/3 also was attenuated, as was Smad-dependent gene transcription. Smad1/5/8-dependent inhibitor
of DNA binding 1 expression and Smad2/3-dependent plasminogen activator inhibitor I expression both were decreased and were
accompanied by decreased cell proliferation. Small interfering RNA–mediated knockdown of endoglin in HS-5 cells verified that
the effects on signaling were a direct result of the attenuation of endoglin. These data illustrate that endoglin acts as
a positive regulator of both activin receptor–like kinase 1–induced Smad1/5/8 activation and activin receptor–like kinase
5–induced Smad2/3 activation in bone marrow stromal cells. In addition, the data illustrate that one early event of metastasis
upon the arrival of prostate cancer cells into the bone stroma is attenuated endoglin expression in the stromal cells, which
subsequently alters Smad signaling and cell proliferation. We hypothesize that coculture of bone marrow stromal cells with
prostate cancer cells alters TGF-β signaling in the stromal cells, ultimately facilitating growth of the cancer cells in the
bone compartment. Collectively, these studies suggest that prostate cancer cells modulate TGF-β responsiveness of bone marrow
stroma as one means of facilitating their own growth in bone. (Mol Cancer Res 2007;5(6):585–603)