Breast Cancer Redox Heterogeneity Detectable with Chemical Exchange Saturation Transfer (CEST) MRI

Abstract

Purpose Tissue redox state is an important mediator of various biological processes in health and diseases such as cancer. Previously, we discovered that the mitochondrial redox state of ex vivo tissues detected by redox scanning (an optical imaging method) revealed interesting tumor redox state heterogeneity that could differentiate tumor aggressiveness. Because the noninvasive chemical exchange saturation transfer (CEST) MRI can probe the proton transfer and generate contrasts from endogenous metabolites, we aim to investigate if the in vivo CEST contrast is sensitive to proton transfer of the redox reactions so as to reveal the tissue redox states in breast cancer animal models. Procedures CEST MRI has been employed to characterize tumor metabolic heterogeneity and correlated with the redox states measured by the redox scanning in two human breast cancer mouse xenograft models, MDA-MB-231 and MCF-7. The possible biological mechanism on the correlation between the two imaging modalities was further investigated by phantom studies where the reductants and the oxidants of the representative redox reactions were measured. Results The CEST contrast is found linearly correlated with NADH concentration and the NADH redox ratio with high statistical significance, where NADH is the reduced form of nicotinamide adenine dinucleotide. The phantom studies showed that the reductants of the redox reactions have more CEST contrast than the corresponding oxidants, indicating that higher CEST effect corresponds to the more reduced redox state. Conclusions This preliminary study suggests that CEST MRI, once calibrated, might provide a novel noninvasive imaging surrogate for the tissue redox state and a possible diagnostic biomarker for breast cancer in the clinic.

CEST signal at 2 ppm (CEST@2ppm) from Z‐spectral fitting correlates with creatine distribution in brain tumor

“…Features observed from the fitted maps agree with the literatures. For example, we observed decreased MTR (36,37), increased water content (38) and increased APT (10) in tumor compared to normal brain tissue. Consistent with the literature, we also observed a negative offset of semi-solid MTR (39) located at around −2ppm from water.…”

Creatine CEST MRI for Differentiating Gliomas with Different Degrees of Aggressiveness

“…For example, we observed decreased MTC [53, 54], higher water content [55], and higher APT [19] in tumors compared to normal brain tissues. We also observed a negative offset of semi-solid MTC located at around −2 ppm from water [49].…”

Magnetization Transfer MRI Contrast May Correlate with Tissue Redox State in Prostate Cancer

“…The propagated cells of human prostate cancer of PC-3 and DU-145 were implanted subcutaneously into the upper thighs of athymic nude mice (~7 million cells/site). Tumor sizes were monitored once a week to obtain tumor volumes ( V = ab 2 /2, where a is the long axis and b is the short axis) [7]. After 5 weeks post implantation, mice bearing DU-145 and PC-3 prostate tumor xenografts ( n = 3 for DU-145 and n = 4 for PC-3 tumors) were scanned at a Varian horizontal 9.4 T MRI scanner.…”

“…Recently, we presented a non-invasive MR imaging method that demonstrated a significant correlation between the tissue redox state and the endogenous chemical exchange saturation transfer (CEST) contrast [7]. CEST MRI, on the basis of the proton exchange between metabolites and tissue bulk water, has been employed to non-invasively imaging tissue amide protons [8], liver glycogen [9], cartilage glycosaminoglycans [10], brain myo-inositol [11], and glutamate [12] with a spatial resolution down to sub-millimeters.…”

“…CEST MRI, on the basis of the proton exchange between metabolites and tissue bulk water, has been employed to non-invasively imaging tissue amide protons [8], liver glycogen [9], cartilage glycosaminoglycans [10], brain myo-inositol [11], and glutamate [12] with a spatial resolution down to sub-millimeters. In our recent study [7], CEST MRI has been employed to characterize intratumoral heterogeneity and to correlate with cancer redox states in xenografts of two breast cancer cell lines, MDA-MB-231 and MCF-7. We found a higher level of intratumoral CEST heterogeneity, calculated as the tumor rim-to-core ratio of CEST, in the aggressive (metastatic) MDA-MB-231 tumors than in the less aggressive (less metastatic or indolent) MCF-7 tumors.…”