Research Papers:

Silencing NIK potentiates anti-VEGF therapy in a novel 3D model of colorectal cancer angiogenesis

Chrissta X. Maracle, Kim C.M. Jeucken, Boy Helder, Thomas M. van Gulik, Anne Steins, Hanneke W.M. van Laarhoven and Sander W. Tas _

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Oncotarget. 2018; 9:28445-28455. https://doi.org/10.18632/oncotarget.25442

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Chrissta X. Maracle1,2,*, Kim C.M. Jeucken1,2,*, Boy Helder1,2, Thomas M. van Gulik3, Anne Steins4, Hanneke W.M. van Laarhoven4 and Sander W. Tas1,2

1Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands

2Laboratory for Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands

3Department of Surgery, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands

4Department of Medical Oncology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands

*These authors contributed equally to this work

Correspondence to:

Sander W. Tas, email: [email protected]

Keywords: tumor angiogenesis; NIK; bevacizumab; colorectal cancer; cytokines

Received: January 15, 2018     Accepted: April 25, 2018     Published: June 19, 2018


Angiogenesis is essential for colorectal cancer (CRC) progression, as demonstrated by the beneficial clinical effects of therapeutics inhibiting VEGF signaling. However, alternative mechanisms of neovascularization can develop, resulting in treatment failure. Previously we demonstrated NF-κB-inducing kinase (NIK) contributes to pathological angiogenesis. Here, we investigate NIK as a therapeutic target in endothelial cells (EC) in CRC. To determine NIK expression levels in CRC tissues, we immunostained both primary colorectal tumors and tumors metastasized to the liver. Additionally, a 3D tumor-stromal cell interaction model was developed including EC, fibroblasts and CRC cells to study tumor angiogenesis. This model tested efficacy of NIK-targeting siRNA (siNIK) in EC alone or in combination with the anti-VEGF antibody, bevacizumab. Both primary CRC and liver metastases contained blood vessels expressing NIK. In patients receiving chemotherapy plus bevacizumab, immature NIK+ vessels (p < 0.05) were increased as compared to chemotherapy alone. Activation of NIK by lymphotoxin-beta receptor (LTβR) induced increases in pro-angiogenic mediators, including interleukin (IL)-6, IL-8, chemokine (C-X-C motif) ligand (CXCL)1 and CXCL5 in EC and fibroblasts, accompanied by sprouting in the 3D model, which was blocked by siNIK in EC. Treatment with bevacizumab plus siNIK in EC resulted in a synergistic effect and reduced VEGF and bFGF-induced sprouting (p < 0.05). Here, we demonstrate a role for NIK in CRC-associated angiogenesis. Targeting NIK in EC in combination with anti-VEGF antibody bevacizumab may hold therapeutic potential to increase efficiency in blocking tumor neovascularization, either to prevent treatment failure due to activation of accessory pathways such as NF-κB signaling or as a rescue treatment.

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