Abstract
The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported. Nor has how p53 regulates mitochondrial respiration been measured at (deep) tissue level, presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth. Our prior work demonstrated that the mitochondrial redox state and its intratumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models, with the more metastatic tumors exhibiting localized regions of more oxidized redox state. Using the Chance redox scanner with an in-plane spatial resolution of 200 μm, we imaged the mitochondrial redox state of the wild-type p53 colon tumors (HCT116 p53 wt) and the p53-deleted colon tumors (HCT116 p53−/−) by collecting the fluorescence signals of nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins [Fp, including flavin adenine dinucleotide (FAD)] from the mouse xenografts snap-frozen at low temperature. Our results show that: (1) both tumor lines have significant degree of intratumor heterogeneity of the redox state, typically exhibiting a distinct bi-modal distribution that either correlates with the spatial core–rim pattern or the “hot/cold” oxidation-reduction patches; (2) the p53−/− group is significantly more heterogeneous in the mitochondrial redox state and has a more oxidized tumor core compared to the p53 wt group when the tumor sizes of the two groups are matched; (3) the tumor size dependence of the redox indices (such as Fp and Fp redox ratio) is significant in the p53−/− group with the larger ones being more oxidized and more heterogeneous in their redox state, particularly more oxidized in the tumor central regions; (4) the H&E staining images of tumor sections grossly correlate with the redox images. The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattern of the mitochondrial redox state in colon cancer and the first to indicate that at tissue level the mitochondrial redox state is p53 dependent. The findings should assist in our understanding on colon cancer pathology and developing new imaging biomarkers for clinical applications.
Highlights
Cancer metabolism has received increasing research interest in recent years
The findings should assist in our understanding on colon cancer pathology and developing new imaging biomarkers for clinical applications
We employed the Chance redox scanner to image the fluorescence of nicotinamide adenine dinucleotide (NADH) and flavoprotein (Fp) with 3D sub-millimeter resolution in two colon cancer lines xenografted in mice, one being p53 wt and the other p53−/−
Summary
Cancer metabolism has received increasing research interest in recent years. Metabolic alteration, a hallmark of cancer, allows cancer cells to adapt to their needs for rapid bioenergetics, increased biogenesis of macromolecules and maintenance of the redox balance.[1] p53, as a tumor suppressor gene, regulates many metabolic pathways including glycolysis and mitochondrial respiration in tumors.[2] p53 plays a central role in mitochondrial oxygen utilization, reactive oxygen species generation, and disposition.[3,4]Previously we demonstrated that tumor meta-static potential was associated with the mitochondrial redox state and its intratumor heterogeneity in both melanoma and breast cancer mouse xenografts models.[5,6,7] We showed that the more metastatic tumors have more oxidized mitochondrial redox state in the localized regions and the quantitative redox indices can grade tumor aggressiveness. We discovered that mitochondrial redox state alteration was linked to the activation of the PI3K/ Akt pathway due to PTEN deletion and cancer transformation.[8] As p53 influences the PI3K/Akt pathway through activating PTEN, it promotes mitochondrial bioenergetics by activating the expression of synthesis of cytochrome c oxidase 2 (SCO2), and inhibits the glycolysis pathway,[3,4,9] we hypothesize that p53 status may affect the mitochondrial redox state To test this hypothesis, we employed the Chance redox scanner to image the fluorescence of nicotinamide adenine dinucleotide (NADH) and flavoprotein (Fp) with 3D sub-millimeter resolution in two colon cancer lines xenografted in mice, one being p53 wt and the other p53−/−. Our findings indicate that the tumor mitochondrial redox state is dependent on p53 status
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