Metabolic syndrome and colon cancer: Is hyperinsulinemia/insulin receptor-mediated angiogenesis a critical process?

Abstract

e14004 Background: Components of the metabolic syndrome (MS) have been individually linked to colon cancer (CC) risk and prognosis. An understanding of the dominant mechanisms is lacking. Methods: 21 patients (10 MS; 11 non-MS) with resectable CC were prospectively enrolled. Patients were classified for MS by the WHO criteria and tested for circulating vascular endothelial growth factor (VEGF), IL-6, insulin-like growth factor-1 (IGF-1), fasting insulin, and tumor expression of IGF-1 receptor (IGF-1R), insulin-receptor (IR) and receptor for advanced glycation end-products (RAGE). Circulating markers were re-tested 6 months after surgery (Sx). Results: The MS group had significantly higher baseline and post-operative fasting insulin levels (p<0.001 and 0.003). No differences were observed in circulating IL-6, VEGF, IGF-1 and free IGF-1. By immunohistochemistry (IHC), IGF-1R expression was significantly higher in tumor vs. normal tissues (p<0.001) while IR expression showed no difference. Interestingly, 7 out of 11 tumors demonstrated high IR positivity in the neovessels within or surrounding the tumor stroma, but not in the vessels away from the tumor. By RT-PCR, tumor IGF-1R over-expression (80%, 12/15) was confirmed, but there was no difference between MS and non-MS patients. Tumor RAGE over-expression was found in 67% (10/15) of patients who equally distributed between the two groups (Table). Conclusions: Hyperinsulinemia was the only significant factor distinguishing CC patients with MS. The preferential overexpression of IR in the peri-tumoral microvessels suggests hyperinsulinemia may contribute to CC growth by enhancing angiogenesis. Comparisons of circulating and tissue markers between MS and non-MS patients. Serum Tissue IGF-1 (ng/L) Free IGF-1 (pg/L) Insulin (uIU/mL) Insulin-R IHC (Allred score) IGF-1R IHC (Allred score) IGF-1R PCR N pre-Sx post-Sx pre-Sx post-Sx pre-Sx post-Sx N Tumor (11) Normal (19) Peri-tumorvessel (7) Tumor (11) Normal (19) N Over-express Under-express MS MedianRange 10 144 145 458 354 12 11 16 3 4 8 7 4 7 7 0 264 111 982 678 20 34 6 7 2 2 2 Non-MS MedianRange 11 118 127 592 361 4 6 14 0 5 8 6.5 4 8 5 3 206 154 431 1037 8 15 4 7 2 2 3