Abstract
SUMMARYHuman prostatic cancer-associated fibroblasts (CAFs) can elicit malignant changes in initiated but non-tumorigenic human prostate epithelium, demonstrating that they possess pro-tumorigenic properties. We set out to reduce the pro-tumorigenic activity of patient CAFs using the Dlk1 and SCUBE1 molecules that we had previously identified in prostate development. Our hypothesis was that mesenchymally expressed molecules might reduce CAF pro-tumorigenic activity, either directly or indirectly. We isolated primary prostatic CAFs and characterised their expression of CAF markers, expression of Notch2, Dlk1 and SCUBE1 transcripts, and confirmed their ability to stimulate BPH1 epithelial cell proliferation. Next, we expressed Dlk1 or SCUBE1 in CAFs and determined their effects upon tumorigenesis in vivo following recombination with BPH1 epithelia and xenografting in SCID mice. Tumour size was reduced by about 75% and BPH1 proliferation was reduced by about 50% after expression of Dlk1 or SCUBE1 in CAFs, and there was also a reduction in invasion of BPH1 epithelia into the host kidney. Inhibition of Notch signalling, using inhibitor XIX, led to a reduction in BPH1 cell proliferation in CAF-BPH1 co-cultures, whereas inhibition of Dlk1 in NIH3T3-conditioned media led to an increase in BPH1 growth. Our results suggest that pro-tumorigenic CAF activity can be reduced by the expression of developmental pathways.
Highlights
The stromal microenvironment plays an important role in prostate development and prostate cancer progression
The authors previously identified several molecules in developing prostate mesenchyme. They set out to determine the effects of these molecules on prostate cancer-associated fibroblasts (CAFs) in an in vivo model system of tumour reconstitution. Their hypothesis was that mesenchymally expressed developmental regulators might inhibit the pro-tumorigenic activities of CAFs – either directly or indirectly
Their data show that expression of Deltalike 1 (Dlk1, a transmembrane protein of the Notch family) or SCUBE1 in CAFs reduced tumour size, epithelial growth and invasion of reconstituted tumours in vivo
Summary
The stromal microenvironment plays an important role in prostate development and prostate cancer progression. Tumour stroma contains activated or carcinoma-associated fibroblasts (CAFs) and stimulates prostate carcinogenesis (Franco et al, 2011; He et al, 2007; Kiskowski et al, 2011; Olumi et al, 1999; Orimo et al, 2005; Tuxhorn et al, 2002). Using tissue recombination and renal capsule xenografting, human prostate CAFs have been shown to induce tumour formation from initiated but non-tumorigenic human prostate epithelial cells (the SV40 immortalised BPH1 cell line), whereas normal prostate fibroblasts (NPFs) did not (Barclay et al, 2005; Olumi et al, 1999). Prostate cancer shows some similarities to embryonic prostate development, notably the importance of stromal-epithelial signalling and of paracrine regulation of stromal and epithelial compartments.
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