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A Fluorescent Hsp90 Probe Demonstrates the Unique Association between Extracellular Hsp90 and Malignancy in Vivo
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posted on 2017-01-19, 00:00 authored by Lauren B. Crowe, Philip F. Hughes, David A. Alcorta, Takuya Osada, Aaron P. Smith, Juliane Totzke, David R. Loiselle, Isaac D. Lutz, Madhusudhana Gargesha, Debasish Roy, Jose Roques, David Darr, H. Kim Lyerly, Neil L. Spector, Timothy A.J. HaysteadExtracellular expression of heat
shock protein 90 (eHsp90) by tumor cells is correlated with malignancy.
Development of small molecule probes that can detect eHsp90 in vivo may therefore have utility in the early detection
of malignancy. We synthesized a cell impermeable far-red fluorophore-tagged
Hsp90 inhibitor to target eHsp90 in vivo. High resolution
confocal and lattice light sheet microscopy show that probe-bound
eHsp90 accumulates in punctate structures on the plasma membrane of
breast tumor cells and is actively internalized. The extent of internalization
correlates with tumor cell aggressiveness, and this process can be
induced in benign cells by overexpressing p110HER2. Whole body cryoslicing,
imaging, and histology of flank and spontaneous tumor-bearing mice
strongly suggests that eHsp90 expression and internalization is a
phenomenon unique to tumor cells in vivo and may
provide an “Achilles heel” for the early diagnosis of
metastatic disease and targeted drug delivery.
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High resolution confocallattice light sheet microscopy showExtracellular Hsp 90probe-bound eHsp 90Vivo Extracellular expressionoverexpressing p 110HERtumor cellstumor cell aggressivenessbreast tumor cellseHsp 90 expressionheat shock protein 90vivocell impermeable far-red fluorophore-tagged Hsp 90 inhibitorFluorescent Hsp 90 Probe Demonstratestarget eHsp 90
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