Abstract

Cancer cells undergo a number of biophysical changes as they transform from an indolent to an aggressive state. These changes, which include altered mechanical and electrical properties, can reveal important diagnostic information about disease status. Here, we introduce a high-throughput, functional technique for assessing cancer cell invasion potential, which works by probing for the mechanically excitable phenotype exhibited by invasive cancer cells. Cells are labeled with fluorescent calcium dye and imaged during stimulation with low-intensity focused ultrasound, a non-contact mechanical stimulus. We show that cells located at the focus of the stimulus exhibit calcium elevation for invasive prostate (PC-3 and DU-145) and bladder (T24/83) cancer cell lines, but not for non-invasive cell lines (BPH-1, PNT1A, and RT112/84). In invasive cells, ultrasound stimulation initiates a calcium wave that propagates from the cells at the transducer focus to other cells, over distances greater than 1 mm. We demonstrate that this wave is mediated by extracellular signaling molecules and can be abolished through inhibition of transient receptor potential channels and inositol trisphosphate receptors, implicating these proteins in the mechanotransduction process. If validated clinically, our technology could provide a means to assess tumor invasion potential in cytology specimens, which is not currently possible. It may therefore have applications in diseases such as bladder cancer, where cytologic diagnosis of tumor invasion could improve clinical decision-making.

Highlights

  • Cancer staging determines both patient prognosis and treatment protocol

  • We have shown that 38-MHz focused ultrasound evokes calcium responses in invasive cancer cells, and we previously reported a similar effect for 200-MHz ultrasound [15]

  • Stimulating at 3 MHz evoked a calcium wave that propagated at 101 μm/s, similar to the speed of the calcium waves induced by 38-MHz stimulation (~50–100 μm/s; see Figures 3A and 4A). These results suggest that the mechanism of ultrasound-induced calcium rise in invasive cancer cells is at least partly independent of stimulus frequency

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Summary

Introduction

Cancer staging determines both patient prognosis and treatment protocol. To stage a biopsied tumor, the pathologist must determine the extent to which the tumor has invaded the surrounding tissue. The intact tissue needed to assess invasion cannot be obtained from the patient In such cases, fine-needle aspirations, washings, or brushings can be performed to collect cells from the tumor for cytologic diagnosis. Fine-needle aspirations, washings, or brushings can be performed to collect cells from the tumor for cytologic diagnosis These cells allow the cytopathologist to Functional Assay of Cancer Invasion determine whether the tumor is benign or malignant, but not whether it is invasive. BCG inflames the bladder epithelium, making it difficult endoscopically to identify recurrent tumors for biopsy [4] In such cases, bladder wash cytology can be used to detect recurrence, but the invasion status of the recurrent malignancy cannot be determined. A method for assessing tumor invasion cytologically (e.g., in bladder washings) would enable appropriate and timely treatments that improve patient outcomes

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