Natriuretic Peptide Receptor A Signaling Regulates Stem Cell Recruitment and Angiogenesis: A Model to Study Linkage Between Inflammation and Tumorigenesis§

Authors

  • Jaya Mallela,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
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  • Sowndharya Ravi,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
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  • Frantz Jean Louis,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
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  • Bianca Mulaney,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
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  • Michael Cheung,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
    3. Division of Translational Medicine, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
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  • Ujjwala Sree Garapati,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
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  • Vignesh Chinnasamy,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
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  • Chunyan Wang,

    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
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  • Srinivas Nagaraj,

    1. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
    2. Division of Translational Medicine, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
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  • Shyam S. Mohapatra,

    1. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
    2. Division of Translational Medicine, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
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  • Subhra Mohapatra

    Corresponding author
    1. Department of Molecular MedicineUniversity of South Florida, Tampa, Florida, USA
    2. Nanomedicine Research CenterUniversity of South Florida, Tampa, Florida, USA
    • 12901 Bruce B Downs Blvd, MDC 7, Room 2525, Tampa, Florida 33612, USA
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    • Telephone: (813) 974-4127; Fax: (813) 974-8575


  • Author contributions: S.M.: conceptual design, data analysis and interpretation, writing manuscript, final approval of manuscript, and financial support; J.M.: collection and assembly of data, data analysis and interpretation, and writing manuscript; S.R.: data collection and assembly; F.J.L.: collection and assembly of data and data analysis and interpretation; B.M.: analysis and interpretation of data; M.C.: data collection, assembly, and analysis and interpretation; U.S.G. and V.C.: data collection and interpretation; C.W.: data analysis and interpretation; S.N.: data analysis, interpretation, and manuscript review; S.S.M.: data analysis, interpretation, and manuscript review. All authors have approved the manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS March 26, 2013.

Abstract

Natriuretic peptide receptor A (NPRA), the signaling receptor for the cardiac hormone, atrial natriuretic peptide (ANP), is expressed abundantly in inflamed/injured tissues and tumors. NPRA deficiency substantially decreases tissue inflammation and inhibits tumor growth. However, the precise mechanism of NPRA function and whether it links inflammation and tumorigenesis remains unknown. Since both injury repair and tumor growth require stem cell recruitment and angiogenesis, we examined the role of NPRA signaling in tumor angiogenesis as a model of tissue injury repair in this study. In in vitro cultures, aortas from NPRA-KO mice show significantly lower angiogenic response compared to wild-type counterparts. The NPRA antagonist that decreases NPRA expression, inhibits lipopolysaccharide-induced angiogenesis. The reduction in angiogenesis correlates with decreased expression of vascular endothelial growth factor and chemokine (C-X-C motif) receptor 4 (CXCR4) implicating a cell recruitment defect. To test whether NPRA regulates migration of cells to tumors, mesenchymal stem cells (MSCs) were administered i.v., and the results showed that MSCs fail to migrate to the tumor microenvironment in NPRA-KO mice. However, coimplanting tumor cells with MSCs increases angiogenesis and tumorigenesis in NPRA-KO mice, in part by promoting expression of CXCR4 and its ligand, stromal cell-derived factor 1α. Taken together, these results demonstrate that NPRA signaling regulates stem cell recruitment and angiogenesis leading to tumor growth. Thus, NPRA signaling provides a key linkage between inflammation and tumorigenesis, and NPRA may be a target for drug development against cancers and tissue injury repair. STEM Cells2013;31:1321–1329

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