Global secretome analysis identifies novel mediators of bone metastasis

Cell Res. 2012 Sep;22(9):1339-55. doi: 10.1038/cr.2012.89. Epub 2012 Jun 12.

Abstract

Bone is the one of the most common sites of distant metastasis of solid tumors. Secreted proteins are known to influence pathological interactions between metastatic cancer cells and the bone stroma. To comprehensively profile secreted proteins associated with bone metastasis, we used quantitative and non-quantitative mass spectrometry to globally analyze the secretomes of nine cell lines of varying bone metastatic ability from multiple species and cancer types. By comparing the secretomes of parental cells and their bone metastatic derivatives, we identified the secreted proteins that were uniquely associated with bone metastasis in these cell lines. We then incorporated bioinformatic analyses of large clinical metastasis datasets to obtain a list of candidate novel bone metastasis proteins of several functional classes that were strongly associated with both clinical and experimental bone metastasis. Functional validation of selected proteins indicated that in vivo bone metastasis can be promoted by high expression of (1) the salivary cystatins CST1, CST2, and CST4; (2) the plasminogen activators PLAT and PLAU; or (3) the collagen functionality proteins PLOD2 and COL6A1. Overall, our study has uncovered several new secreted mediators of bone metastasis and therefore demonstrated that secretome analysis is a powerful method for identification of novel biomarkers and candidate therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor / analysis
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Collagen Type VI / metabolism
  • Computational Biology
  • Humans
  • Mass Spectrometry
  • Mice
  • Neoplasms / pathology
  • Plasminogen Activators / metabolism
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / metabolism
  • Proteome / analysis*
  • Proteomics
  • Salivary Cystatins / metabolism

Substances

  • Biomarkers, Tumor
  • CST1 protein, human
  • CST2 protein, human
  • CST4 protein, human
  • Col6a1 protein, human
  • Collagen Type VI
  • Proteome
  • Salivary Cystatins
  • PLOD2 protein, human
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Plasminogen Activators