Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

BACKGROUND: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. METHODS: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT-PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. RESULTS: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. CONCLUSION: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis

Role of nutritional status and intervention in oesophageal cancer treated with definitive chemoradiotherapy:outcomes from SCOPE1

BACKGROUND: Malnutrition is common in oesophageal cancer. We aimed to identify nutritional prognostic factors and survival outcomes associated with nutritional intervention in the SCOPE1 (Study of Chemoradiotherapy in OesoPhageal Cancer with or without Erbitux) trial. METHODS: Two hundred and fifty eight patients were randomly allocated to definitive chemoradiotherapy (dCRT) +/− cetuximab. Nutritional Risk Index (NRI) scores were calculated; NRI<100 identified patients at risk of malnutrition. Nutritional intervention included dietary advice, oral supplementation or major intervention (enteral feeding/tube placement). Univariable and multivariable analyses using Cox proportional hazard modelling were conducted. RESULTS: At baseline NRI<100 strongly predicted for reduced overall survival (hazard ratio (HR) 12.45, 95% CI 5.24–29.57; P<0.001). Nutritional intervention improved survival if provided at baseline (dietary advice (HR 0.12, P=0.004), oral supplementation (HR 0.13, P<0.001) or major intervention (HR 0.13, P=0.003)), but not if provided later in the treatment course. Cetuximab patients receiving major nutritional intervention had worse outcomes compared with controls (13 vs 28 months, P=0.003). CONCLUSIONS: Pre-treatment assessment and correction of malnutrition may improve survival outcomes in oesophageal cancer patients treated with dCRT. Nutritional Risk Index is a simple and objective screening tool to identify patients at risk of malnutrition