Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential

Abstract

Background Tumour acidosis is considered to play a central role in promoting cancer invasion and migration, but few studies have investigated in vivo how tumour pH correlates with cancer invasion. This study aims to determine in vivo whether tumour acidity is associated with cancer metastatic potential. Methods Breast cancer cell lines with different metastatic potentials have been characterised for several markers of aggressiveness and invasiveness. Murine tumour models have been developed and assessed for lung metastases and tumour acidosis has been assessed in vivo by a magnetic resonance imaging-based chemical exchange saturation transfer (CEST) pH imaging approach. Results The higher metastatic potential of 4T1 and TS/A primary tumours, in comparison to the less aggressive TUBO and BALB-neuT ones, was confirmed by the highest expression of cancer cell stem markers (CD44+CD24−), highlighting their propensity to migrate and invade, coinciding with the measurement obtained by in vitro assays. MRI-CEST pH imaging successfully discriminated the more aggressive 4T1 and TS/A tumours that displayed a more acidic pH. Moreover, the observed higher tumour acidity was significantly correlated with an increased number of lung metastases. Conclusions The findings of this study indicate that the extracellular acidification is associated with the metastatic potential.

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

“…Differences in position may possibly account the difference observed between both techniques. It is also worth to mention that the basal pHe values (before treatment) measured in our study for the 4T1 tumor model were higher than 7.0 (for CEST-MRI and 31 P-NMR) while a recent study that compared several breast cancer cell lines suggested lower pHe values for the same model (6.96 ± 0.03) [ 27 ]. Different experimental conditions may potentially explain these differences: different conditions of cell culture before inoculation and time-window for the MRI study during the tumor growth.…”

“…Different experimental conditions may potentially explain these differences: different conditions of cell culture before inoculation and time-window for the MRI study during the tumor growth. We also noticed that the anesthesia used was different: ketamine/xylazine in the reference study [ 27 ] and isoflurane in the present study. As ketamine/xylazine is known to induce a rapid drop in tumor perfusion and oxygenation [ 50 , 51 , 52 ], we hypothesize that this experimental factor may potentially contribute to subtle difference in glycolytic activity and pHe values recorded for the same tumor model.…”

“…A ratiometric procedure allows to measure pHe independently on the concentration of iopamidol in the pH range of 6.0 to 8.0. This technique has been used in a variety of tumor models [ 23 , 24 , 25 , 26 , 27 ] and in cancer patients [ 28 , 29 ]. The technique has also been used to monitor the changes in pHe in tumors induced by treatments such as administration of bicarbonate [ 30 , 31 ] or after the pyruvate dehydrogenase kinase inhibitor dichloroacetate [ 32 ].…”

Putting Warburg to work: how imaging of tumour acidosis could help predict metastatic potential in breast cancer

“…These include microelectrodes, which are invasive and imprecise, positron emission tomography approaches, which report on a composite of pH e and pH i , and genetically encoded or injectable optical imaging techniques, which are often not clinically relevant and remain limited by the lack of sufficiently specific near-infrared pH e probes. 1,2 In this issue of the British Journal of Cancer, Anemone et al 7 used magnetic resonance imaging (MRI)-based, pH-sensitive chemical exchange saturation transfer (MRI-CEST) 8,9 to demonstrate that extracellular acidosis correlates with tumour metastatic behaviour in vivo. Employing spontaneous BALB-neuT mammary tumours as well as syngeneic engrafting of metastatic and non-metastatic mammary cancer cell lines in BALB/c mice, they created spatial pH e maps of primary tumours and defined an acidity score highlighting pH e heterogeneity.…”

“…While earlier studies have proposed a correlation between invasiveness and extracellular acidity in tumours, 12,13 the work by Anemone et al 7 takes this an important step further by combining the precision and clinical potential -MRI-CEST has been used in patients 14 of MRI-CEST with studies of mammary cancer phenotype. Notably, they found that the tumour acidity score correlated not only with metastasis, but also with the expression of cancer stem cell markers in the tumour tissue, extending earlier reports that stemness in glioma models is dependent on an acidic niche pH e .…”