1. ¹Department of Urology, University of Virginia, Charlottesville, VA, USA
2. ²Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
3. ³Department of Pathology, University of Virginia, Charlottesville, VA, USA
4. ⁴Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
5. ⁵Vascular Biology Center, Medical College of Georgia, University of Virginia, Charlottesville, VA, USA
6. ⁶Paul Mellon Urologic Cancer Institute, University of Virginia, Charlottesville, VA, USA

Correspondence: Professor Dr D Theodorescu, Departments of Urology, and Molecular Physiology and Biological Physics, University of Virginia, Health Sciences Center, Box 800422, Charlottesville, VA 22908, USA. E-mail: dt9d@virginia.edu

⁷Current address: Abraxis BioScience, 4503 Glencoe Avenue, Marina del Rey, CA 90292, USA

Received 20 October 2008; Revised 24 February 2009; Accepted 26 April 2009; Published online 13 July 2009.

Abstract

SPARC (Secreted Protein Acidic and Rich in Cysteine), is a matricellular glycoprotein that is produced by tumor and/or neighboring stroma. In human prostate cancer, SPARC immunoreactivity is highest in metastatic lesions but distinct contributions of tumoral and stromal SPARC to tumorigenesis and progression are unclear. To determine the role of SPARC in primary prostate tumorigenesis, we crossed SPARC-null (SP^-/-) with TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. TRAMP⁺/SP^-/- mice exhibited accelerated cancer development and progression. Compared to their TRAMP⁺/SP^-/- counterparts, TRAMP⁺/SP^+/+ tumors had fewer proliferating cells, and decreased cyclins A and D1 with increased p21^Cip and p27^Kip. Similar effects on proliferation and cell-cycle regulators were observed in human prostate cancer cell lines, transiently transfected with pSPARC. TRAMP⁺/SP^-/- tumors exhibited decreased stromal collagen, enhanced matrix metalloproteinase activity and increased vascular endothelial growth factor, proinflammatory cytokines. To determine the contribution of stromal SPARC, we evaluated subcutaneous tumor growth of TRAMP cell lines in syngeneic SP^+/+ and SP^-/- mice. Enhanced growth, decreased stromal collagen and increased proteolysis were noted in SP^-/- mice. Our findings demonstrate that both tumor and stromal SPARC are limiting for primary prostate tumorigenesis and progression, through effects on the cell cycle and the creation of a less favorable tumor microenvironment.