Abstract
The tumor microcirculation is characterized by an abnormal vascular network with dilated, tortuous and saccular vessels. Therefore, imaging the tumor vasculature and determining its morphometric characteristics represent a critical goal for optimizing the cancer treatment that targets the blood vessels (i.e. antiangiogenesis therapy). The aim of this study was to evaluate new vascular morphometric parameters in colorectal cancer, difficult to achieve through conventional immunohistochemistry, by using the confocal laser endomicroscopy method. Fresh biopsies from tumor and normal tissue were collected during colonoscopy from five patients with T3 colorectal carcinoma without metastasis and were marked with fluorescently labeled anti-CD31 antibodies. A series of optical slices spanning 250 µm inside the tissue were immediately collected for each sample using a confocal laser endomicroscope. All measurements were expressed as the mean ± standard error. The mean diameter of tumor vessels was significantly larger than the normal vessels (9.46±0.4 µm vs. 7.60±0.3 µm, p = 0.0166). The vessel density was also significantly higher in the cancer vs. normal tissue samples (5541.05±262.81 vs. 3755.79±194.96 vessels/mm3, p = 0.0006). These results were confirmed by immunohistochemistry. In addition, the tortuosity index and vessel lengths were not significantly different (1.05±0.016 and 28.30±3.27 µm in normal tissue, vs. 1.07±0.008 and 26.49±3.18 µm in tumor tissue respectively, p = 0.5357 and p = 0.7033). The daughter/mother ratio (ratio of the sum of the squares of daughter vessel radii over the square of the mother vessel radius) was 1.15±0.09 in normal tissue, and 1.21±0.08 in tumor tissue (p = 0.6531). The confocal laser endomicroscopy is feasible for measuring more vascular parameters from fresh tumor biopsies than conventional immunohistochemistry alone. Provided new contrast agents will be clinically available, future in vivo use of CLE could lead to identification of novel biomarkers based on the morphometric characteristics of tumor vasculature.
Highlights
The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels [1], [2]
We evaluated new vascular network parameters difficult to assess with conventional immunohistochemistry in patients with clinically staged T3 primary colorectal carcinoma, without metastatic spread, by using Confocal Laser Endomicroscopy (CLE) combined with fluorescently labeled anti-CD31 antibodies for labeling of both normal and tumor blood vessels
Confocal Laser Endomicroscopy The CLE procedure gave a detailed observation of adjacent tumor and normal mucosa sections with visible fluorescent signal (Fig. 1)
Summary
The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels [1], [2]. The tumor vascularization and in particular the growth of new vessels (angiogenesis) has attracted increased attention in the last two decades for possible applications to diagnosis, prognosis stratification and targeted treatment [1]. Among methods to assess tumor vascularization, the determination of microvessel density (MVD) from immunohistochemistry (IHC) samples is commonly used in preclinical and clinical studies. MVD represents the average number of vessels per mm within a tissue sample but that measure alone is insufficient for monitoring vascular changes over a treatment period [3]. Other functional and morphologic parameters such as blood volume, permeability, microvessel density, vessel diameter, branching patterns, other measures of vessel shape and tumor metabolism can be associated with tumor angiogenesis. Antiangiogenic agents that disrupt the vascular endothelial growth factor pathway have been demonstrated to normalize tumor vasculature
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