In Vivo Profiling the Chemical Tumor Microenvironment for Diagnosis and Therapy

We hypothesized Janus-faced properties of chemical tumor microenvironment (cTME) [1], proposing that specific patterns of tissue oxygenation (pO₂), extracellular pH (pH_e), redox and intracellular glutathione (GSH) homeostasis act to utilize an orchestrated mechanism to promote cancer cell survival while at the same time being highly toxic and mutagenic for normal cells. Therefore, noninvasive in vivo assessment of these parameters provides important knowledge for advanced TME-targeted anticancer therapies. We utilized electron paramagnetic resonance (EPR)-based spectroscopy and imaging for cTME profiling in mouse models of various cancers including in vivo assessment of tissue redox, GSH, pO₂, pH_e, and concentration of interstitial phosphate (Pi) using functional paramagnetic probes [2-4]. cTME profiling were performed as tumor progresses to malignancy and during application of metabolically active drugs. The in vivo studies performed in breast tumor-bearing mice show that all the measured parameters, pO₂, pH, Pi, redox and GSH, tend to deviate from the pattern characteristic of normal tissue upon progression to malignancy. Normalizing the cTME parameters correlated with partial inhibition of tumor growth, therefore providing a tool for TME-targeted anticancer therapy. A capacity of specific cTME pattern to be used as a prognostic factor in tumorigenesis and the approaches for normalizing chemical tumor microenvironment for anticancer TME-targeted therapeutic interventions will be discussed. Supported by NIH grant EB014542 and CA194013.

[1] Khramtsov VV; Gillies RJ. Janus-Faced Tumor Microenvironment and Redox. Antioxid Redox Signal., 2014, 21, 723-729.

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[4] Bobko AA et al. Angew. Chem. Int. Edit. 2014, 53, 2735-2738.