Interstitial Inorganic Phosphate as a Tumor Microenvironment Marker for Tumor Progression

Abstract

Noninvasive in vivo assessment of chemical tumor microenvironment (TME) parameters such as oxygen (pO2), extracellular acidosis (pHe), and concentration of interstitial inorganic phosphate (Pi) may provide unique insights into biological processes in solid tumors. In this work, we employ a recently developed multifunctional trityl paramagnetic probe and electron paramagnetic resonance (EPR) technique for in vivo concurrent assessment of these TME parameters in various mouse models of cancer. While the data support the existence of hypoxic and acidic regions in TME, the most dramatic differences, about 2-fold higher concentrations in tumors vs. normal tissues, were observed for interstitial Pi - the only parameter that also allowed for discrimination between non-metastatic and highly metastatic tumors. Correlation analysis between [Pi], pO2, pHe and tumor volumes reveal an association of high [Pi] with changes in tumor metabolism and supports different mechanisms of protons and Pi accumulation in TME. Our data identifies interstitial inorganic phosphate as a new TME marker for tumor progression. Pi association with tumor metabolism, buffer-mediated proton transport, and a requirement of high phosphorus content for the rapid growth in the “growth rate hypothesis” may underline its potential role in tumorigenesis and tumor progression.

Unveiling a hidden 31P signal coresonating with extracellular inorganic phosphate by outer‐volume‐suppression and localized 31P MRS in the human brain at 7T

“…Such measurements in humans have been challenging technically but are critical for understanding normal brain processes, as well as the pathophysiology of a variety of brain conditions and diseases such as tumors and traumatic brain injury. [5][6][7][8][9][10][11][12][13][14]…”

Exchange Phenomena in the Electron Paramagnetic Resonance Spectra of the Nitroxyl and Trityl Radicals: Multifunctional Spectroscopy and Imaging of Local Chemical Microenvironment

“…28,29 Note interstitial extracellular localization of the pTAM probe: it does not penetrate into the cells due to bulky charged structures and the pTAM signal from the blood is not detected by EPR due to signal broadening by pTAM complexation with plasma albumin. 70 Reproduced from ref 71 with permission of Nature Publishing Group. Copyright 2017 Nature Publishing Group…”

“…A negative correlations between p O 2 and Pi both in (b) normal tissue ( r = −0.51, p = 0.013 for black symbols; r = −0.7, p = 2.3 × 10 −5 for total data set), and (d) in TME (b, bottom: r = −0.4, p = 0.079 for black symbols; r = −0.62, p = 0.001 for total data set) were found. Adapted from ref 71 with permission. Copyright 2017 Springer Nature.…”

In Vivo Application of Proton-Electron Double-Resonance Imaging

“…Recently, trityl probe with spectral sensitivity to pH, pO 2 , and Pi (inorganic phosphate) in an extracellular tissue microenvironment (termed HOPE probe, see Fig. 16b) has been synthesized (10,26) and used for concurrent multifunctional assessment of TME in tumor-bearing mice by using low-field EPR spectroscopy (11). In our opinion, the PEDRI approach in combination with the HOPE probe provides an opportunity for multifunctional mapping of a tissue microenvironment in living subjects.…”