Temporal Heterogeneity in Blood Supply in Human Tumor Xenografts

Abstract

Temporal heterogeneities in tumor blood supply were studied by using a recently developed first-pass imaging technique. First-pass imaging movies of A-07-GFP human tumor xenografts growing in window chambers were recorded at a frame rate of approximately 9 fps and a spatial resolution of 10.8 x 10.8 microm(2) after a bolus of 155-kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. Each tumor was subjected to imaging thrice, with 20 minutes between each repetition. Highly specific maps of the vascular network and blood supply time (BST) images (i.e., images of the time from when arterial blood enters a tumor through the main supplying artery until it reaches a vessel segment within the tumor) were produced from the movies. The tumors had one to three supplying arterioles and showed substantial temporal heterogeneity in BST. Homogeneous changes in BST in the entire vascular network were seen in tumors supplied by one arteriole. Blood supply time fluctuations in tumor subregions were observed in tumors having two or three supplying arterioles. In addition, individual vessel segments frequently showed significant changes in BST with time. High-magnification transmission microscopy imaging substantiated that BST changes could be a consequence of arterial/arteriolar vasomotor activity, vessel wall compression, varying flow rate, and vascular stasis.

Spectral imaging reveals microvessel physiology and function from anastomoses to thromboses

“…49 Research to characterize acute fluctuations in tumor microvessel oxygenation and perfusion requires advanced imaging techniques with microvessel resolution. 50 Spectral imaging of tumor microvessel oxygenation may be a useful tool in this effort. We previously showed that spectral imaging could be used to measure acute fluctuations in tumor microvessel oxygenation.…”

The changing paradigm of tumour response to irradiation

“…This was a widely observed phenomenon in both transplanted and spontaneously arising tumours. [48][49][50] It was subsequently shown that tumours usually contain regions subject to fluctuating blood flow, 51,52 leading to the concept that tumour cells may be exposed to either chronic or acute (cycling) hypoxic environments and that observed reoxygenation could be partially explained by such cycling hypoxia. Chronic hypoxia is largely thought to occur as a result of oxygen diffusion limitations, but potentially, it may also result from the presence of unusually long vessels or slow blood flow when the oxygen capacity of the blood may be exhausted along the length of the vessel.…”

Mechanisms of Radioresistance in Cancer Stem Cells

“…Prolonged or chronic hypoxia is regarded as "diffusion-limited" hypoxia in which tumor cells are located far away from the vascular supply, whereas acute hypoxia in tumors is considered as "perfusionlimited" hypoxia, in which tumor oxygenation fluctuates over time [54][55][56]. Hypoxia in tumors is a well-established poor prognostic indicator as it promotes aggressive transformation of tumor cells leading to enhanced metastatic potential [57][58][59], and it is well recognized that hypoxic tumor cells are more radioresistant than nonhypoxic cells [60].…”