Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

• Published in: NMR in biomedicine Vol. 27; no. 7; pp. 760 - 773
• Main Authors: Springer Jr, Charles S., Li, Xin, Tudorica, Luminita A., Oh, Karen Y., Roy, Nicole, Chui, Stephen Y-C., Naik, Arpana M., Holtorf, Megan L., Afzal, Aneela, Rooney, William D., Huang, Wei
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2014; Wiley Subscription Services, Inc; BlackWell Publishing Ltd
• Subjects: Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cell Size; Contrast Media; Female; heterogeneity; Humans; Intracellular Space - metabolism; intratumor; Kinetics; Magnetic Resonance Imaging - methods; metabolic activity; Permeability; therapy; Water; intratumor; maps; therapy; heterogeneity; metabolic activity
• ISSN: 0952-3480; 1099-1492
• DOI: 10.1002/nbm.3111

Shutter‐speed pharmacokinetic analysis of dynamic‐contrast‐enhanced (DCE)‐MRI data allows evaluation of equilibrium inter‐compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τi). The τi biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE‐MRI. We present population‐averaged in vivo human breast whole tumor τi changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while Ktrans (measuring mostly contrast agent (CA) extravasation) and kep (CA intravasation rate constant) decrease, τi increases. However, high‐resolution, (1 mm)2, parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τi value means a trans‐membrane water cycling flux of 1013 H2O molecules s−1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy‐induced changes) of τi in combination with concomitant changes of ve (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, PW, not of cell size. These can be interpreted in light of literature results showing that τi changes are dominated by a PW(active) component that reciprocally reflects the membrane driving P‐type ATPase ion pump turnover. For mammalian cells, this is the Na+,K+‐ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd. Shutter‐speed (but not tracer) pharmacokinetic analyses of in vivo human breast cancer dynamic‐contrast‐enhanced MRI data provide high‐resolution maps of the intracellular water lifetime (τi). This quantity shows great intratumor heterogeneity, and increases with effective therapy. Evidence is presented that τi is a reciprocal measure of cytolemmal water permeability, most likely dominated by active trans‐membrane water cycling driven by on‐going Na+,K+‐ATPase turnover.