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. 2017:2017:4972078.
doi: 10.1155/2017/4972078. Epub 2017 May 3.

Inhibition of Lysyl Oxidases Impairs Migration and Angiogenic Properties of Tumor-Associated Pericytes

Aline Lopes Ribeiro  1 , Carolini Kaid  1 , Patrícia B G Silva  1 , Beatriz A Cortez  1 , Oswaldo Keith Okamoto  1
Affiliations

Inhibition of Lysyl Oxidases Impairs Migration and Angiogenic Properties of Tumor-Associated Pericytes

Aline Lopes Ribeiro et al. Stem Cells Int. 2017.

Abstract

Pericytes are important cellular components of the tumor microenviroment with established roles in angiogenesis and metastasis. These two cancer hallmarks are modulated by enzymes of the LOX family, but thus far, information about LOX relevance in tumor-associated pericytes is lacking. Here, we performed a comparative characterization of normal and tumoral pericytes and report for the first time the modulatory effects of LOX enzymes on activated pericyte properties. Tumoral pericytes isolated from childhood ependymoma and neuroblastoma specimens displayed angiogenic properties in vitro and expressed typical markers, including CD146, NG2, and PDGFRβ. Expression of all LOX family members could be detected in both normal and tumor-associated pericytes. In most pericyte samples, LOXL3 was the family member displaying the highest transcript levels. Inhibition of LOX/LOXL activity with the inhibitor β-aminopropionitrile (βAPN) significantly reduced migration of pericytes, while proliferation rates were kept unaltered. Formation of tube-like structures in vitro by pericytes was also significantly impaired upon inhibition of LOX/LOXL activity with βAPN, which induced more prominent effects in tumor-associated pericytes. These findings reveal a novel involvement of the LOX family of enzymes in migration and angiogenic properties of pericytes, with implications in tumor development and in therapeutic targeting tumor microenvironment constituents.

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Figures

Figure 1
Figure 1
Angiogenic properties of pericytes. Both normal (NP-Ad, NP-Mu) and tumor-associated pericytes (TP-Nbl, TP-Epn) were capable of forming tube-like structures in vitro, generating interconnected networks similar to those generated by endothelial cells (HUVEC). Mesenchymal stem cells (MSCs) do not share this propriety and, therefore, were not able to generate such tube-like structures under the same experimental conditions. (a) NP-Ad; (b) NP-Mu; (c) TP-Nbl; (d) TP-Epn; (e) HUVEC; (f) MSC.
Figure 2
Figure 2
Activated properties of normal and tumor-associated pericytes. (a) Cell migration was calculated after 6 h in the presence of chemical stimulus, relative to basal cell migration without chemotaxis. (b) Cell proliferation based on BrdU incorporation after 24 h in culture. Kinetics of tube-like formation by (c) normal pericytes and (d) tumor-associated pericytes, under angiogenic conditions in vitro. Normal pericyte samples: NP-Ad and NP-Mu. Tumor-associated pericyte samples: TP-Nbl and TP-Epn. Significance level: ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001.
Figure 3
Figure 3
Comparative analysis of LOX and LOXL1–4 expression profiles in normal and tumor-associated pericytes. Gene expression was assessed by quantitative real-time PCR, using TBP as endogenous control. Normal pericyte samples: NP-Ad and NP-Mu. Tumor-associated pericyte samples: TP-Nbl and TP-Epn. Endothelial cells (HUVEC) and mesenchymal stem cells (MSCs) were also included in the analysis as control samples. (a) NP-Ad; (b) NP-Mu; (c) TP-Nbl; (d) TP-Epn; (e) HUVEC; (f) MSC. Significance level: ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001.
Figure 4
Figure 4
LOX and LOXL3 protein levels in normal and tumor-associated pericytes. Representative Western blots for each protein are shown. Normal pericyte samples: NP-Ad and NP-Mu. Tumor-associated pericyte samples: TP-Nbl and TP-Epn.
Figure 5
Figure 5
Effects of βAPN on migration and proliferation of normal and tumor-associated pericytes. (a) Cell migration measured after 24 h treatment with 1 μM βAPN. (b) Cell proliferation based on BrdU incorporation after 24 h and 48 h treatment with 1 μM βAPN. Normal pericyte samples: NP-Ad and NP-Mu. Tumor-associated pericyte samples: TP-Nbl and TP-Epn. Significance level: ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001.
Figure 6
Figure 6
Effects of βAPN on angiogenic properties of normal and tumor-associated pericytes. The kinetics of tube-like formation by pericytes was assessed for 24 hours under treatment with 1 μM βAPN in vitro. Normal pericyte samples: NP-Ad and NP-Mu. Tumor-associated pericyte samples: TP-Nbl and TP-Epn. (a) NP-Ad; (b) NP-Mu; (c) TP-Nbl; (d) TP-Epn.
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References

    1. Chen F., Zhuang X., Lin L., et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Medicine. 2015;13:p. 45. doi: 10.1186/s12916-015-0278-7. - DOI - PMC - PubMed
    1. Hanahan D., Weinberg R. A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. - DOI - PubMed
    1. Bolouri H. Network dynamics in the tumor microenvironment. Seminars in Cancer Biology. 2015;30(2):52–59. doi: 10.1016/j.semcancer.2014.02.007. - DOI - PubMed
    1. Klemm F., Joyce J. A. Microenvironmental regulation of therapeutic response in cancer. Trends in Cell Biology. 2015;25(4):198–213. doi: 10.1016/j.tcb.2014.11.006. - DOI - PMC - PubMed
    1. Ungefroren H., Sebens S., Seidl D., Lehnert H., Hass R. Interaction of tumor cells with the microenvironment. Cell Communication and Signaling: CCS. 2011;9(1):p. 18. doi: 10.1186/1478-811X-9-18. - DOI - PMC - PubMed

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