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. 2019 May;21(5):572-581.
doi: 10.1007/s12094-018-1955-8. Epub 2018 Oct 6.

Anti-tumor effect of endostatin in a sleep-apnea mouse model with tumor

X-B Zhang  1   2   3   4 , Y-Y Yang  1   2 , Y Zeng  5   6 , H-Q Zeng  7   8 , B-B Fu  1   2   9 , C-Y Ko  3   4 , X Luo  10 , Y-P Du  1   2 , L-D Chen  11 , Y-T Lai  1   2 , Y Wu  1   2
Affiliations

Anti-tumor effect of endostatin in a sleep-apnea mouse model with tumor

X-B Zhang et al. Clin Transl Oncol. 2019 May.

Abstract

Background: Obstructive sleep apnea (OSA) is associated with cancer incidence and mortality. The underlying mechanism is unclear. This study aims to evaluate the influence of intermittent hypoxia (IH), a novel hallmark of OSA, on tumor and to access the anti-tumor effect of endostatin on a mouse model with OSA.

Methods: The C57BL/6 J mice were randomly classified into four groups: control (normoxia) (CTL), control plus endostatin (CTL + ED), IH, and IH plus endostatin (IH + ED). Mice in IH and IH + ED groups were subjected to IH 8 h per day in 5 weeks. Lewis lung cancer cells were injected into the flank of each mouse after 1 week of IH exposure. Endostatin was also intraperitoneally injected after tumor volume reached about 200 mm3. The maximum standard uptake values (SUVmax) were detected by micro-positron emission tomography-computed tomography (micro-PET-CT) imaging prior and post-endostatin administration. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were determined for evaluating the anti-tumor effect of endostatin among the normoxia and IH conditions.

Results: Mice had higher SUVmax in the IH group than the CTL group (p < 0.01). When compared with mice in the CTL group, those in the IH group had significantly greater MVD values (p < 0.001). The SUVmax can be attenuated by endostatin both in the CTL (p < 0.01) and IH conditions (p < 0.001). When compared with CTL group, mice in the IH group had increased MVD values (p < 0.001) and VEGF expression both at mRNA (p < 0.05) and protein levels (p < 0.001 in western blotting results). Treatment with endostatin attenuated serum and tissue VEGF levels, lowering the MVD values. As compared to normoxia condition, the endostatin-therapeutic effects were more significant under the IH condition (p < 0.05 in western blotting results).

Conclusions: Micro-PET-CT imaging is a promising non-invasive technique to evaluate the tumor metabolic characteristics under IH condition in vivo. The anti-tumor effect of endostatin under IH condition is superior to that of the normoxia condition.

Keywords: Endostatin; Intermittent hypoxia; Positron emission tomography; Sleep apnea; Tumor.

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