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The role of SPARC in the TRAMP model of prostate carcinogenesis and progression

Oncogene volume 28, pages 3487–3498 (2009)Cite this article

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 p21Cip and p27Kip. 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.

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Acknowledgements

This work was supported by NIH CA104106 (DT) and Georgia Cancer Coalition grant GCC0023 (KM) and the National Institutes of Health grants K01-CA089689 (KM).

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Author notes

  1. K Motamed

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

Authors and Affiliations

  1. Department of Urology, University of Virginia, Charlottesville, VA, USA

    N Said, D Chernauskas & D Theodorescu

  2. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA

    N Said, D Chernauskas & D Theodorescu

  3. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    H F Frierson Jr

  4. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    M Conaway

  5. Vascular Biology Center, Medical College of Georgia, University of Virginia, Charlottesville, VA, USA

    K Motamed

  6. Paul Mellon Urologic Cancer Institute, University of Virginia, Charlottesville, VA, USA

    D Theodorescu

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Correspondence to D Theodorescu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Said, N., Frierson, H., Chernauskas, D. et al. The role of SPARC in the TRAMP model of prostate carcinogenesis and progression. Oncogene 28, 3487–3498 (2009). https://doi.org/10.1038/onc.2009.205

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