Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model

Ruggiero, María; Baroni, Simona; Bitonto, Valeria; Ruiu, Roberto; Rapisarda, Smeralda; Aime, Silvio; Crich, Simonetta Geninatti

doi:10.3389/fonc.2021.778823

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…In fact, tumor tissue has unusual protein structure and concentrations that may influence the water motion and its molecular dynamics, as well as its extra- and intracellular water exchanges. Interestingly, FFC showed a good capability to discriminate cancer in term of aggressiveness [ 11 ] with the potential to characterize tumor margins [ 12 ] and response to treatment [ 13 ] and, more specifically, to discriminate invasion from proliferation [ 14 ]. The latter study validated a relationship between the relaxation-rate constant (R1 = 1/T1) at very low magnetic field and the pathophysiological processes of glioma on ex vivo tissues of experimental glioma mouse models.…”

Section: Introductionmentioning

confidence: 99%

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field

Ruggiero

Itto

Baroni

et al. 2022

Cancers

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This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions.

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Section: Introductionmentioning

confidence: 99%

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field

Ruggiero

Itto

Baroni

et al. 2022

Cancers

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“…3a ), thus excluding a direct inhibitory effect of the ATPase pump. The functional activity of Na + /K + ATPase, evaluated as Rb + uptake capacity 17 in the course of Monensin treatment without exogenously added ATP, highlighted an early, though not significant, reduction of the Rb + uptake (Fig. 3b ) that was parallel to ATP depletion (Fig.…”

Section: Resultsmentioning

confidence: 95%

Boosting intracellular sodium selectively kills hepatocarcinoma cells and induces hepatocellular carcinoma tumor shrinkage in mice

Clemente,

Baroni,

Fiorilla

et al. 2023

Commun Biol

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Pharmacological treatments for advanced hepatocellular carcinoma (HCC) have a partial efficacy. Augmented Na+ content and water retention are observed in human cancers and offer unexplored targets for anticancer therapies. Na+ levels are evaluated upon treatments with the antibiotic cation ionophore Monensin by fluorimetry, ICP-MS, 23Na-MRI, NMR relaxometry, confocal or time-lapse analysis related to energy production, water fluxes and cell death, employing both murine and human HCC cell lines, primary murine hepatocytes, or HCC allografts in NSG mice. Na+ levels of HCC cells and tissue are 8-10 times higher than that of healthy hepatocytes and livers. Monensin further increases Na+ levels in HCC cells and in HCC allografts but not in primary hepatocytes and in normal hepatic and extrahepatic tissue. The Na+ increase is associated with energy depletion, mitochondrial Na+ load and inhibition of O2 consumption. The Na+ increase causes an enhancement of the intracellular water lifetime and death of HCC cells, and a regression and necrosis of allograft tumors, without affecting the proliferating activity of either HCCs or healthy tissues. These observations indicate that HCC cells are, unlike healthy cells, energetically incapable of compensating and surviving a pharmacologically induced Na+ load, highlighting Na+ homeostasis as druggable target for HCC therapy.

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“…Previous in vitro studies have estimated water exchange for several cell types under different physiological conditions, including yeast, 6 red blood cells, 16 glial cells, 17 and breast cancer cells. 18,19 As in DCE-MRI studies, these studies follow a similar approach of using a gadolinium-based contrast agent (GBCA) to create a sufficient difference in T 1 between the intracellular and extracellular spaces, sensitizing the T 1 -weighted data, commonly acquired using an inversion or saturation recovery experiment, to cellular water exchange. These data have been analyzed using the two-site exchange (2SX) model 11 to estimate the water efflux rate k ie , which is a reciprocal of the intracellular water lifetime (τ i ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the in vivo studies, in vitro NMR studies have provided a crucial insight into cellular water exchange. Previous in vitro studies have estimated water exchange for several cell types under different physiological conditions, including yeast, 6 red blood cells, 16 glial cells, 17 and breast cancer cells 18,19 . As in DCE‐MRI studies, these studies follow a similar approach of using a gadolinium‐based contrast agent (GBCA) to create a sufficient difference in T 1 between the intracellular and extracellular spaces, sensitizing the T 1 ‐weighted data, commonly acquired using an inversion or saturation recovery experiment, to cellular water exchange.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous estimation of the cellular water exchange rate, intracellular volume fraction, and longitudinal relaxation rate in cancer cells

et al. 2023

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The purpose of the current study was to investigate the feasibility of simultaneously estimating the cellular water efflux rate ( kie), intracellular longitudinal relaxation rate ( R10i), and intracellular volume fraction ( vi) of a cell suspension using multiple samples with different gadolinium concentrations. Numerical simulation studies were conducted to assess the uncertainty in the estimation of kie, R10i, and vi from saturation recovery data using single (SC) or multiple concentrations (MC) of gadolinium‐based contrast agent (GBCA). In vitro experiments with 4 T1 murine breast cancer and SCCVII squamous cell cancer models were conducted at 11 T to compare parameter estimation using the SC protocol with that using the MC protocol. The cell lines were challenged with a Na+/K+‐ATPase inhibitor, digoxin, to assess the treatment response in terms of kie, R10i, and vi. Data analysis was conducted using the two‐compartment exchange model for parameter estimation. The simulation study data demonstrate that the MC method, compared with the SC method, reduces the uncertainty of the estimated kie by decreasing the interquartile ranges from 27.3% ± 3.7% to 18.8% ± 5.1% and the median differences from ground truth from 15.0% ± 6.3% to 7.2% ± 4.2%, while estimating R10i and vi simultaneously. In the cell studies, the MC method demonstrated reduced uncertainty in overall parameter estimation compared with the SC approach. MC method‐measured parameter changes in cells treated with digoxin increased R10i by 11.7% (p = 0.218) and kie by 5.9% (p = 0.234) for 4 T1 cells, respectively, and decreased R10i by 28.8% (p = 0.226) and kie by 1.6% (p = 0.751) for SCCVII cells, respectively. vi did not change noticeably by the treatment. The results of this study substantiate the feasibility of using saturation recovery data of multiple samples with different GBCA concentrations for simultaneous measurement of the cellular water efflux rate, intracellular volume fraction, and intracellular longitudinal relaxation rate in cancer cells.

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Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model

Cited by 8 publications

References 44 publications

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field

Boosting intracellular sodium selectively kills hepatocarcinoma cells and induces hepatocellular carcinoma tumor shrinkage in mice

Simultaneous estimation of the cellular water exchange rate, intracellular volume fraction, and longitudinal relaxation rate in cancer cells

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