Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors—including Snail, HIF-1, ZEB1, and STAT3—that are activated by signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.

/pdf/induction-of-metastasis-cancer-stem-cell-phenotype-and-318usj2fx3.pdf

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation

Light propagating in tissue attains a spectrum that varies with location due to wavelength-dependent fluence attenuation, an effect that causes spectral corruption. Spectral corruption has limited the quantification accuracy of optical and optoacoustic spectroscopic methods, and impeded the goal of imaging blood oxygen saturation (sO2) deep in tissues; a critical goal for the assessment of oxygenation in physiological processes and disease. Here we describe light fluence in the spectral domain and introduce eigenspectra multispectral optoacoustic tomography (eMSOT) to account for wavelength-dependent light attenuation, and estimate blood sO2 within deep tissue. We validate eMSOT in simulations, phantoms and animal measurements and spatially resolve sO2 in muscle and tumours, validating our measurements with histology data. eMSOT shows substantial sO2 accuracy enhancement over previous optoacoustic methods, potentially serving as a valuable tool for imaging tissue pathophysiology.

Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues

The benevolent and detrimental effects of antioxidants are much debated in clinical trials and cancer research. Several antioxidant enzymes and molecules are overexpressed in oxidative stress conditions that can damage cellular proteins, lipids, and DNA. Natural antioxidants remove excess free radical intermediates by reducing hydrogen donors or quenching singlet oxygen and delaying oxidative reactions in actively growing cancer cells. These reducing agents have the potential to hinder cancer progression only when administered at the right proportions along with chemo-/radiotherapies. Antioxidants and enzymes affect signal transduction and energy metabolism pathways for the maintenance of cellular redox status. A decline in antioxidant capacity arising from genetic mutations may increase the mitochondrial flux of free radicals resulting in misfiring of cellular signalling pathways. Often, a metabolic reprogramming arising from these mutations in metabolic enzymes leads to the overproduction of so called ’oncometabolites’ in a state of ‘pseudohypoxia’. This can inactivate several of the intracellular molecules involved in epigenetic and redox regulations, thereby increasing oxidative stress giving rise to growth advantages for cancerous cells. Undeniably, these are cell-type and Reactive Oxygen Species (ROS) specific, which is manifested as changes in the enzyme activation, differences in gene expression, cellular functions as well as cell death mechanisms. Photodynamic therapy (PDT) using light-activated photosensitizing molecules that can regulate cellular redox balance in accordance with the changes in endogenous ROS production is a solution for many of these challenges in cancer therapy.

https://www.mdpi.com/2076-3921/9/11/1156/pdf

Redox Potential of Antioxidants in Cancer Progression and Prevention.

Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells

Because radiotherapy significantly increases median survival in patients with glioblastoma, the modulation of radiation resistance is of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance; thus, the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Metabolically, the elevated glycolysis in glioblastoma cells was observed postradiotherapy together with upregulated hypoxia-inducible factor (HIF)-1α and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate, a PDK inhibitor currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. Dichloroacetate alone demonstrated modest antitumor effects in both in vitro and in vivo models of glioblastoma and has the ability to reverse the radiotherapy-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of glioblastoma cells was observed when dichloroacetate was combined with radiotherapy. Further mechanistic investigation revealed that dichloroacetate sensitized glioblastoma cells to radiotherapy by inducing the cell-cycle arrest at the G2-M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in glioblastoma cells together with radiotherapy. In vivo, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma-bearing mice. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of dichloroacetate and radiotherapy in clinical trials.

https://mct.aacrjournals.org/content/molcanther/14/8/1794.full.pdf

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Radiation induces aerobic glycolysis through reactive oxygen species.

We demonstrate an optical strategy using intravital microscopy of dorsal skin flap window chamber models to image glucose uptake and vascular oxygenation in vivo. Glucose uptake was imaged using a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). SO2 was imaged using the differential absorption properties of oxygenated [HbO2] and deoxygenated hemoglobin [dHb]. This study was carried out on two sibling murine mammary adenocarcinoma lines, 4T1 and 4T07. 2-NBDG uptake in the 4T1 tumors was lowest when rates of delivery and clearance were lowest, indicating perfusion-limited uptake in poorly oxygenated tumor regions. For increasing rates of delivery that were still lower than the glucose consumption rate (as measured in vitro), both 2-NBDG uptake and the clearance rate from the tumor increased. When the rate of delivery of 2-NBDG exceeded the glucose consumption rate, 2-NBDG uptake decreased with any further increase in rate of delivery, but the clearance rate continued to increase. This inflection point was not observed in the 4T07 tumors due to an absence of low delivery rates close to the glucose consumption rate. In the 4T07 tumors, 2-NBDG uptake increased with increasing rates of delivery at low rates of clearance. Our results demonstrate that 2-NBDG uptake in tumors is influenced by the rates of delivery and clearance of the tracer. The rates of delivery and clearance are, in turn, dependent on vascular oxygenation of the tumors. Knowledge of the kinetics of tracer uptake as well as vascular oxygenation is essential to make an informed assessment of glucose demand of a tumor.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0076524&type=printable

Delivery rate affects uptake of a fluorescent glucose analog in murine metastatic breast cancer.

We report the development of non-invasive, fiber-based diffuse optical spectroscopy for simultaneously quantifying vascular oxygenation (SO2) and glucose uptake in solid tumors in vivo Glucose uptake was measured using a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG) Quantification of label-free SO2 and 2-NBDG-fluorescence-based glucose uptake 60 minutes after administration of the tracer (2-NBDG60) was performed using computational models of light-tissue interaction This study was carried out on normal tissue and 4T1 and 4T07 murine mammary tumor xenografts in vivo Injection of 2-NBDG did not cause a significant change in optical measurements of SO2, demonstrating its suitability as a functional reporter of tumor glucose uptake Correction of measured 2-NBDG-fluorescence for the effects of absorption and scattering significantly improved contrast between tumor and normal tissue The 4T1 and 4T07 tumors showed significantly decreased SO2, and 4T1 tumors demonstrated increased 2-NBDG60 compared with normal tissue (60 minutes after the administration of 2-NBDG when perfusion-mediated effects have cleared) 2-NBDG-fluorescence was found to be highly sensitive to food deprivation-induced reduction in blood glucose levels, demonstrating that this endpoint is indeed sensitive to glycolytic demand 2-NBDG60 was also found to be linearly related to dose, underscoring the importance of calibrating for dose when comparing across animals or experiments 4T1 tumors demonstrated an inverse relationship between 2-NBDG60 and SO2 that was consistent with the Pasteur effect, particularly when exposed to hypoxic gas breathing Our results illustrate the potential of optical spectroscopy to provide valuable information about the metabolic status of tumors, with important implications for cancer prognosis

/pdf/non-invasive-simultaneous-quantification-of-vascular-2o0tbir6nn.pdf

Non-invasive, simultaneous quantification of vascular oxygenation and glucose uptake in tissue.

When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, “RD”, reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a “Warburgian” (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo.

/pdf/delivery-corrected-imaging-of-fluorescently-labeled-glucose-2b6afui7qi.pdf

Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer

Objective

Hemodynamic properties of vascular beds are of great interest in a variety of clinical and laboratory settings. However, there presently exists no automated, accurate, technically simple method for generating blood velocity maps of complex microvessel networks.



Methods

Here, we present a novel algorithm that addresses the problem of acquiring quantitative maps by applying pixel-by-pixel cross-correlation to video data. Temporal signals at every spatial coordinate are compared with signals at neighboring points, generating a series of correlation maps from which speed and direction are calculated. User-assisted definition of vessel geometries is not required, and sequential data are analyzed automatically, without user bias.



Results

Velocity measurements were validated against the dual-slit method and against in vitro capillary flow with known velocities. The algorithm was tested in three different biological models in order to demonstrate its versatility.



Conclusions

The hemodynamic maps presented here demonstrate an accurate, quantitative method of analyzing dynamic vascular systems.

/pdf/quantitative-mapping-of-hemodynamics-in-the-lung-brain-and-1hmxr52xlj.pdf

Quantitative Mapping of Hemodynamics in the Lung, Brain, and Dorsal Window Chamber-Grown Tumors Using a Novel, Automated Algorithm

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