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Sci Rep. 2015 Mar 19;5:9327. doi: 10.1038/srep09327.

Circulating peptidome to indicate the tumor-resident proteolysis.

Author information

1
1] School of Life Science, Tsinghua University, Beijing 100084, China [2] Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue R8-213, Houston, TX 77030, United States [3] Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
2
Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue R8-213, Houston, TX 77030, United States.
3
Institute of Biophysics, Chinese Academy Of Sciences, 15 Datum Road, Chaoyang District, Beijing 100101, China.
4
1] School of Life Science, Tsinghua University, Beijing 100084, China [2] Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
5
1] Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue R8-213, Houston, TX 77030, United States [2] Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 445 E. 69th Street, New York, New York 10021, United States.
6
1] Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue R8-213, Houston, TX 77030, United States [2] Department of Internal Medicine, Weill Cornell Medical College of Cornell University, 445 E. 69th Street, New York, New York 10021, United States.

Abstract

Tumor-resident proteases (TRPs) are regarded as informative biomarkers for staging cancer progression and evaluating therapeutic efficacy. Currently in the clinic, measurement of TRP is dependent on invasive biopsies, limiting their usefulness as monitoring tools. Here we identified circulating peptides naturally produced by TRPs, and evaluated their potential to monitor the efficacy of anti-tumor treatments. We established a mouse model for ovarian cancer development and treatment by orthotopic implantation of the human drug-resistant ovarian cancer cell line HeyA8-MDR, followed by porous silicon particle- or multistage vector (MSV) - enabled EphA2 siRNA therapy. Immunohistochemistry staining of tumor tissue revealed decreased expression of matrix metallopeptidase 9 (MMP-9) in mice exhibiting positive responses to MSV-EphA2 siRNA treatment. We demonstrated, via an ex vivo proteolysis assay, that C3f peptides can act as substrates of MMP-9, which cleaves C3f at L1311-L1312 into two peptides (SSATTFRL and LWENGNLLR). Importantly, we showed that these two C3f-derived fragments detected in serum were primarily generated by tumor-resident, but not blood-circulating, MMP-9. Our results suggested that the presence of the circulating fragments specially derived from the localized cleavage in tumor microenvironment can be used to evaluate therapeutic efficacy of anti-cancer treatment, assessed through a relatively noninvasive and user-friendly proteomics approach.

PMID:
25788424
PMCID:
PMC4365414
DOI:
10.1038/srep09327
[Indexed for MEDLINE]
Free PMC Article

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