A Fluorescent Hsp90 Probe Demonstrates the Unique Association between Extracellular Hsp90 and Malignancy in Vivo.
Lauren B CrowePhilip F HughesDavid A AlcortaTakuya OsadaAaron P SmithJuliane TotzkeDavid R LoiselleIsaac D LutzMadhusudhana GargeshaDebasish RoyJose RoquesDavid DarrH Kim LyerlyNeil L SpectorTimothy A J HaysteadPublished in: ACS chemical biology (2017)
Extracellular 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.
Keyphrases
- heat shock protein
- high resolution
- small molecule
- living cells
- heat shock
- poor prognosis
- drug delivery
- fluorescent probe
- quantum dots
- single cell
- single molecule
- cell therapy
- heat stress
- induced apoptosis
- cancer therapy
- squamous cell carcinoma
- optical coherence tomography
- small cell lung cancer
- mass spectrometry
- binding protein
- signaling pathway
- protein protein
- high throughput
- high glucose
- skeletal muscle
- stem cells
- mesenchymal stem cells
- drug induced
- long non coding rna
- fluorescence imaging
- label free
- photodynamic therapy
- insulin resistance
- wild type