Abstract
BackgroundThe present study aimed to investigate the role of blood supply in early tumorigenesis in colorectal cancer. We leveraged the renin angiotensin system (RAS) to alter colonic blood supply and determine the effect on tumor initiation and progression.MethodsTo test the effect of blood supply on tumorigenesis, 53 male A/J mice were randomly assigned to one of three RAS modulation groups and one of two AOM treatments. The RAS modulation groups were I) water (RAS-unmodulated) as a control group, II) angiotensin-II and III) the angiotensin receptor blocker, Losartan. The mice in each group were then randomly split into either the saline control condition or the AOM-treated condition in which tumors were induced with a standard protocol of serial azoxymethane (AOM) injections. To monitor microvascular changes in the rectal mucosa during the study, we used confocal laser endomicroscopy (CLE) with FITC-Dextran for in-vivo imaging of vessels and polarization-gated spectroscopy (PGS) to quantify rectal hemoglobin concentration ([Hb]) and blood vessel radius (BVR).ResultsAt 12 weeks post-AOM injections and before tumor formation, CLE images revealed many traditional hallmarks of angiogenesis including vessel dilation, loss of co-planarity, irregularity, and vessel sprouting in the pericryptal capillaries of the rectal mucosa in AOM-Water tumor bearing mice. PGS measurements at the same time-point showed increased rectal [Hb] and decreased BVR. At later time points, CLE images showed pronounced angiogenic features including irregular networks throughout the colon. Notably, the AOM-Losartan mice had significantly lower tumor multiplicity and did not exhibit the same angiogenic features observed with CLE, or the increase in [Hb] or decrease in BVR measured with PGS. The AOM-AngII mice did not have any significant trends.ConclusionIn-vivo PGS measurements of rectal colonic blood supply as well as CLE imaging revealed angiogenic disruptions to the capillary network prior to tumor formation. Losartan demonstrated an effective way to mitigate the changes to blood supply during tumorigenesis and reduce tumor multiplicity. These effects can be used in future studies to understand the early vessel changes observed.
Highlights
The present study aimed to investigate the role of blood supply in early tumorigenesis in colorectal cancer
Increases in hemoglobin concentration ([Hb]) and density of red blood cells were quantified with polarization-gated spectroscopy (PGS), a novel, depth-selective optical technique developed by our group [8]
Using PGS in vivo, we identified potential field carcinogenesis markers of blood supply and noted that in the microscopically normal rectal mucosa of patients harboring more proximal neoplasia, the superficial micro-circulation was increased, even at distances greater than 30 cm from the malignant lesion [4]
Summary
The present study aimed to investigate the role of blood supply in early tumorigenesis in colorectal cancer. Vasodilation and increased microvascular density (MVD), quantified through histological examination, were detected as underlying causes of augmented blood content at the pre-adenoma stage [9]. These architectural and dynamic changes represent field carcinogenesis ( referred to as field effect) that could be exploited to improve diagnostic detection. Using PGS in vivo, we identified potential field carcinogenesis markers of blood supply and noted that in the microscopically normal rectal mucosa of patients harboring more proximal neoplasia, the superficial micro-circulation (within 100 μm of colonic luminal surface) was increased, even at distances greater than 30 cm from the malignant lesion [4]. Additional studies have confirmed markers of field carcinogenesis, including increased blood supply in microscopically normal-appearing rectal mucosa of patients with advanced adenomas in the more proximal colon [11,12,13,14]
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