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Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor

Oncogene volume 40, pages 4809–4819 (2021)Cite this article

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Abstract

For patients with anaplastic Wilms tumor (WiT), metastasis and recurrence are common, and prognosis is generally poor. Novel therapies are needed to improve outcomes for patients with this high-risk WiT. A potential contributor to WiT development is constitutive activation of AKT by insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) signaling pathway, but the complete underlying mechanism remains unclear. Here, we demonstrate that the hypoxia-inducible factor 1α (HIF-1α)-IGF binding protein 2 (IGFBP2) axis and the tumor-specific IGF1A are key players for constitutive activation of IGF1-AKT signaling leading to the tumor malignancy. HIF-1α and IGFBP2 are highly expressed in a majority of WiT patient samples. Deficiency of either HIF-1α or IGFBP2 or IGF1 in the tumor cells significantly impairs tumor growth and nearly abrogates metastasis in xenografted mice. Pharmacologic targeting of HIF-1α by echinomycin delivered via nanoliposomes can efficiently restrain growth and metastasis of patient-derived relapsed anaplastic WiT xenografts. Liposomal echinomycin is more potent and effective in inhibiting WiT growth than vincristine in an anaplastic WiT mouse model, and eliminates metastasis by suppressing HIF-1α targets and the HIF-1α-IGFBP2 axis, which governs IGF1-AKT signaling.

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Fig. 1: HIF-1α is highly accumulated and activated in pediatric WiT.
Fig. 2: HIF-1α expression is critical for WiT growth.
Fig. 3: Lipo-EM inhibits growth and metastasis of WiT more efficiently than vincristine.
Fig. 4: IGFBP2 is a downstream target gene controlled by HIF-1α.
Fig. 5: HIF-1α and IGFBP2 are critical for WiT growth and metastasis.
Fig. 6: IGF1 drives the growth and metastasis of WiT49 cells in vivo.
Fig. 7: HIF-1α-IGFBP2 axis enhances IGF1-IGF1R-AKT signaling for HIF-1α accumulation and feedforward regulation which are targetable by echinomycin in WiT.

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Acknowledgements

This study was supported by the grants from the National Institutes of Health National Cancer Institute CA171972, CA183030 (Y.L.), and CA219150, CA227671 (Y.W.).

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  1. These authors contributed equally: Yan Liu, Marie V. Nelson.

Authors and Affiliations

  1. Division of Cancer and Immunology Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA

    Yan Liu, Christopher Bailey, Peng Zhang, Pan Zheng, Yang Liu & Yin Wang

  2. Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, USA

    Marie V. Nelson & Jeffrey S. Dome

  3. OncoC4, Inc, Rockville, MD, USA

    Pan Zheng & Yang Liu

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Contributions

Y. Liu: Conceptualization, data curation, formal analysis, supervision, investigation, methodology, writing original manuscript, and writing-review and editing. M.V. Nelson: Clinical sample collection, investigation, data curation, writing-original draft, and review and editing. C. Bailey: Investigation, data curation, methodology and review and editing. P. Zhang: bioinformatics analyses. J.S. Dome, P. Zheng: Formal analysis, supervision, writing-review and editing. Y. Liu, Y. Wang: Conceptualization, formal analysis, supervision, funding acquisition, project administration, writing-review and editing.

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Correspondence to Yan Liu, Yang Liu or Yin Wang.

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Liu, Y., Nelson, M.V., Bailey, C. et al. Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor. Oncogene 40, 4809–4819 (2021). https://doi.org/10.1038/s41388-021-01907-1

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