The Effect of Notch, IL‐1 and Leptin (NILCO) Inhibition in Xenograft Colorectal Cancer

Abstract

The aim of this study was to investigate the effects of inhibition of Notch, IL‐1 and leptin systems on tumorigenesis and angiogenesis in xenograft colorectal cancer model. This study was conducted with the approval of the EU/2010/63 directive and the Greek Presidential Decree 56/2013 (Approval No. 5542/228006/1). In each group, 40 scid (NOD/SCID) mice with 6–8 weeks of age were studied in 5 groups. For tumor formation 1 × 107 human colon cancer cells HCT‐15 were injected subcutaneously into the dorsal flank of the mice. When the tumor size was 100–250 mm3, treatment was started. Group 1: Leptin receptor antagonist ALLO‐aca was injected with 1mg / kg / day subcutaneously (s.c) for 15 days (n: 8). Group 2: γ‐secretase inhibitor DAPT was injected with 10 mg / kg / day subcutaneously (s.c) for 15 days (n: 8). Group 3: Recombinant human IL‐1 receptor antagonist (IL‐1Ra) was injected with 1mg / kg / day subcutaneously (s.c) for 15 days (n: 8). Group 4: 4% DMSO/Safflower Oil (DAPT solvent) was injected subcutaneously (s.c) for 15 days. (n: 8). Group 5: 10% DMSO/0,9%NaCl (Allo aca and IL‐1 iınhibitor solvent) was injected subcutaneously (s.c) for 15 days. (n: 8). After 15 days, tissues were collected and gene expression experiments were performed. mRNA abundance of leptin, leptin OB‐RL receptor, Notch1 receptor, JAGGED1 ligand, IL‐1β, IL‐1R tI, VEGF‐A, VEGFR2 conducted by qRT‐PCR. According to PCR results, leptin, its receptor Ob‐R, Notch1, JAGGED1, VEGF‐A and VEGFR1 mRNA abundance were decreased only in the DAPT group (respectively; p<0.05, p<0.05, p<0.05, p<0.01, p<0.05, p<0.01). The mRNA abundance of VEGFR2 was decreased only in the IL‐1 inhibitor group (p<0.05). According to the results, DAPT at 10 mg / kg / day dose Notch receptor and its ligand was reduced as well as decreased mRNA abundance of leptin and VEGF systems that pro‐angiogenogenic factors. The results of our study support the oncogenic role of Notch, IL‐1 and Leptin crosstalk in colorectal cancer. Inhibition of NILCO signaling could lead to the development of new adjuvant therapies to reduce or eliminate tumor angiogenesis.Support or Funding InformationThis study is supported by a grant from Eskisehir Osmangazi University Scientific Research Projects (Project no:2017‐11028)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.