Abstract
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.
Highlights
Over the past decades, colorectal cancer (CRC) incidence has steadily risen and is currently the third most common type of such malignancy, accounting for approximately 10% of cancer related deaths in Western countries [1, 2]
NF-κB-inducing kinase (NIK)+ blood vessels are present in CRC liver metastasis with increased levels of immature NIK+ vessels in patients treated with bevacizumab
Using colorectal cancer metastases removed during liver surgery, we found that NIK stabilization was occurring in blood vessels at these sites of secondary tumor growth (Figure 1C), whereas it was not observed in healthy liver (Figure 1D)
Summary
Colorectal cancer (CRC) incidence has steadily risen and is currently the third most common type of such malignancy, accounting for approximately 10% of cancer related deaths in Western countries [1, 2]. Vascular endothelial growth factor (VEGF) is a key cytokine in blood vessel formation and is a therapeutic target of the monoclonal antibody bevacizumab, currently one of the most widely used inhibitors of angiogenesis. Resistance to VEGF inhibition generally develops through compensatory mechanisms of angiogenesis, including activation of alternative signaling pathways in endothelial cells (EC) by other growth factors and/ or inflammatory molecules. The latter can activate surrounding stromal and immune cells within the tumor microenvironment, helping to further ignite and enhance tumor neovascularization [11, 12]
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