Implementing successful colon cancer chemopreventive strategies involve finding sensitive and reliable biochemical targets for chemoprevention and biomarkers that validate its progress well before the onset of late uncurable phase of carcinogenesis. On these lines, with our recently developed four-dimensional light scattering fingerprinting (4D-ELF) technique, we for the first time detected early increase in sub-epithelial blood supply at a time point that preceedes the formation of any established histological or morphological markers of colon cancer. These effects initiate near the epithelial mucosa and progress deep into the mucosa/submucosa region. With high sensitivity and specificity, early increase in blood supply (EIBS) was observed in both animal and human CRC, substantiating its potential as a reliable biomarker. Increased blood supply (e.g. angiogenesis) in rapidly growing tumor during colonic carcinogenesis is well known but the stage at which it initiates remains unclear. Recent studies, utilizing semi-quantiative determinations, indicate angiogenesis as early as aberrant crypt foci stage, suggesting that alterations in blood supply may precede macroscopic neoplastic lesions. It is argued that premalignant epithelial cells being hyperproliferative (as a manifestation of """"""""field effect"""""""") also requires increased blood supply to nourish rapid cellular growth. Mechanism by which early mucosal transformation leads to EIBS is not clear but it could be related to increased vasodilation and/or formation of new vessels. Our preliminary data strongly suggests that the pleiotrophic modulator nitric oxide (NO), that regulates microvessel properties and is implicated in neoplastic transformation, may be critical for EIBS induction so as to maintain the metabolic needs of the mucosal cells, progressing through early carcinogenic events. In this application we further want to explore the hypothesis that EIBS may be a sustained response to nitric oxide signaling that initiates early carcinogenic transformation. To test the hypothesis we will utilize APCMIN mouse, a well validated genetic model of CRC and evaluate the relationship of NO with EIBS during preneoplastic phase. Mucosal nitric oxide will be assayed directly and by enzymatic means and related to EIBS as measured by 4D-ELF. Pharmacological block of NO will be used to establish its direct relationship with EIBS. These mechanistic studies will establish the relationship of colon carcinogenesis with EIBS as a potential intermediate biomarker. ? ? ?
| Wali, Ramesh K; Kunte, Dhananjay P; Koetsier, Jennifer L et al. (2008) Polyethylene glycol-mediated colorectal cancer chemoprevention: roles of epidermal growth factor receptor and Snail. Mol Cancer Ther 7:3103-11 |
| Roy, Hemant K; Wali, Ramesh K; Kim, Young et al. (2007) Inducible nitric oxide synthase (iNOS) mediates the early increase of blood supply (EIBS) in colon carcinogenesis. FEBS Lett 581:3857-62 |
