An Epidermal Growth Factor Motif of Developmental Endothelial Locus 1 Protein Inhibits Efficient Angiogenesis in Explanted Squamous Cell Carcinoma In Vivo

Abstract

Background: Cancer gene therapy using a nonviral vector is expected to be repeatable, safe, and inexpensive, and to have longterm effectiveness. Gene therapy using the E3 and C1 (E3C1) domain of developmental endothelial locus-1 (Del1) has been shown to improve prognosis in a mouse transplanted tumor model. Objective: In this study, we examined how this treatment affects angiogenesis in mouse transplanted tumors. Materials and methods: Mouse transplanted tumors (SCCKN human squamous carcinoma cell line) were injected locally with a nonviral plasmid vector encoding E3C1 weekly. Histochemical analysis of the transplanted tumors was then performed to assess the effects of E3C1 on prognosis. Results: All mice in the control group had died or reached an endpoint within 39 days. In contrast, one of ten mice in the E3C1 group had died by day 39, and eight of ten had died or reached an endpoint by day 120 (p < 0.01). Enhanced apoptosis in tumor stroma was seen on histochemical analyses, as was inhibited tumor angiogenesis in E3C1-treated mice. In addition, western blot analysis showed decreases in active Notch and HEY1 proteins. Conclusion: These findings indicate that cancer gene therapy using a nonviral vector encoding E3C1 significantly improved lifespan by inhibiting tumor angiogenesis. (REV INVEST CLIN. [AHEAD OF PRINT]

Developmental endothelial locus-1 in cardiovascular and metabolic diseases: a promising biomarker and therapeutic target

“…Intramuscular delivery of a plasmid expressing DEL-1 and the control significantly improved baseline exercise capacity at 30, 90, and 180 days, but there was no difference in outcome measures between the two groups. DEL-1-mediated angiogenesis has also been reported in many other diseases, such as ischemia models, lung adenocarcinoma, retinopathy, squamous cell carcinoma, and psoriasis [119,[124][125][126][127][128][129]. Taken together, these data suggest that DEL-1-regulated angiogenesis may be a target for many diseases, but its clinical value requires further clinical trials to demonstrate.…”

Developmental endothelial locus-1 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target

“…Intramuscular delivery of a plasmid expressing DEL-1 and the control significantly improved baseline exercise capacity at 30, 90, and 180 days, but there was no difference in outcome measures between the two groups. DEL-1-mediated angiogenesis has also been reported in many other diseases, such as ischemia models, lung adenocarcinoma, retinopathy, squamous cell carcinoma, and psoriasis ( 119 , 124 – 129 ). Taken together, these data suggest that DEL-1-regulated angiogenesis may be a target for many diseases, but its clinical value requires further clinical trials.…”

The EGF Motif With CXDXXXXYXCXC Sequence Suppresses Fibrosis in a Mouse Skin Wound Model

“…Explanted tumor models were generated as described previously (14)(15)(16)(17)(18). Briefly, Nu/Nu athymic nude mice were injected subcutaneously in the right flank with squamous cell carcinoma KN (SCCKN) cells.…”

“…The stroma is essential for parenchymal growth in cancer, as it supplies blood vessels and nutritional support to cancer cells (13). Kitano et al reported that forced expression of a recombinant protein with the third epithelial growth factor (EGF)-like domain (E3) of developmental endothelial locus-1 (Del1), an extracellular matrix protein secreted by endothelial cells, suppressed the growth of explanted squamous cell carcinoma tumors in a mouse model (14)(15)(16)(17)(18). The EGF-like domain includes the amino acid sequence CXDXXXXYXCXC, which reportedly induces apoptosis (19).…”

“…The EGF-like domain includes the amino acid sequence CXDXXXXYXCXC, which reportedly induces apoptosis (19). Treatment with EGF-like domain was shown to induce apoptosis in the parenchyma and stroma, resulting in poor stromal development in explanted tumors (14,15). The similarities between cancer growth and wound healing led us to hypothesize that treatment with EGF domains with a CXDXXXXYXCXC sequence would suppress the growth of mesenchymal tissue in wound healing.…”