Abstract
Vascular supply is a critical component of the tumor microenvironment (TME) and is essential for tumor growth and metastasis, yet the endogenous genetic modifiers that impact vascular function in the TME are largely unknown. To identify the host TME modifiers of tumor vascular function, we combined a novel genetic mapping strategy [Consomic Xenograft Model] with near-infrared (NIR) fluorescence imaging and multiparametric analysis of pharmacokinetic modeling. To detect vascular flow, an intensified cooled camera based dynamic NIR imaging system with 785 nm laser diode based excitation was used to image the whole-body fluorescence emission of intravenously injected indocyanine green dye. Principal component analysis was used to extract the spatial segmentation information for the lungs, liver, and tumor regions-of-interest. Vascular function was then quantified by pK modeling of the imaging data, which revealed significantly altered tissue perfusion and vascular permeability that were caused by host genetic modifiers in the TME. Collectively, these data demonstrate that NIR fluorescent imaging can be used as a non-invasive means for characterizing host TME modifiers of vascular function that have been linked with tumor risk, progression, and response to therapy.
Highlights
NIR optical fluorescence imaging has been extensively exploited for molecular and functional imaging in small animals models and continues to be explored for additional clinical applications of fluorescence guided lymphatic and intra-operative imaging [1, 2] Because of the high sensitivity [3] and low tissue autofluorescence in NIR, optical imaging can characterize dynamic events/changes in tissue with suitable contrast agents, and has been demonstrated for longitudinally tracking multiple pathologies and therapy response [4,5,6,7,8,9]
Combined with our previous histological data demonstrating that the SS.BN3IL2Rγ tumors have increased vascular density and tortuosity [24, 25], these data suggest that the host genetic microenvironment of the SS.BN3IL2Rγ rat induces nonproductive angiogenesis that is reflected by the slower Indocyanine green (ICG) washout
Principal Component Analysis (PCA) helps in better visualization of tumor area and allows to select Regions of interest (ROIs) with MATLAB image processing toolbox function ‘roipoly. The pK parameters obtained from tumor region (MDA-methylene blue (MB)-231) are shown in Fig. 3(a)-3(f) where the top row represents SSIL2Rγ tumors and the bottom row represents SS.BN3IL2Rγ tumors
Summary
NIR optical fluorescence imaging has been extensively exploited for molecular and functional imaging in small animals models and continues to be explored for additional clinical applications of fluorescence guided lymphatic and intra-operative imaging [1, 2] Because of the high sensitivity [3] and low tissue autofluorescence in NIR, optical imaging can characterize dynamic events/changes in tissue with suitable contrast agents, and has been demonstrated for longitudinally tracking multiple pathologies and therapy response [4,5,6,7,8,9]. ROIs on tumors can be visually drawn for subcutaneous tumors in nude mice, it is challenging to identify and segment orthotopic tumors and internal organs from epifluorescence images without PCA decomposition, especially in animal models larger than 20g nude mice
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