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Modeling the Effects of Hemodynamic Stress on Circulating Tumor Cells using a Syringe and Needle

During metastasis, cancer cells from solid tissues, including epithelia, gain access to the lymphatic and hematogenous circulation where they are exposed ...

University of Iowa

Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young's modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm) and low (510 dyn/cm) FSS. The PrEC LH cells were ~140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ~77% in Young's modulus after exposure to high FSS and a ~47% increase in Young's modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young's modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young's modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future.

Alterations in cancer cell mechanical properties after fluid shear stress exposure: a micropipette aspiration study.

Circulating tumor cells (CTCs) exist in a microenvironment quite different from the solid tumor tissue microenvironment. They are detached from matrix and exposed to the immune system and hemodynamic forces leading to the conclusion that life as a CTC is "nasty, brutish, and short." While there is much evidence to support this assertion, the mechanisms underlying this are much less clear. In this chapter we will specifically focus on biomechanical influences on CTCs in the circulation and examine in detail the question of whether CTCs are mechanically fragile, a commonly held idea that is lacking in direct evidence. We will review multiple lines of evidence indicating, perhaps counterintuitively, that viable cancer cells are mechanically robust in the face of exposures to physiologic shear stresses that would be encountered by CTCs during their passage through the circulation. Finally, we present emerging evidence that malignant epithelial cells, as opposed to their benign counterparts, possess specific mechanisms that enable them to endure these mechanical stresses.

Biomechanics of the Circulating Tumor Cell Microenvironment.

During metastasis, cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level FSS in vitro relative to non-transformed epithelial cells. Herein, we identify a mechano-adaptive mechanism of FSS resistance in cancer cells. Our findings demonstrate that cancer cells activate RhoA in response to FSS, which protects them from FSS-induced plasma membrane damage. We show that cancer cells freshly isolated from mouse and human tumors are resistant to FSS, that formin and myosin II activity protects circulating tumor cells (CTCs) from destruction, and that short-term inhibition of myosin II delays metastasis in mouse models. Collectively, our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.

Benjamin L. Krog

Department of Molecular Physiology and Biophysics,
Carver College of Medicine,
Department of Molecular Physiology and Biophysics, Carver College of Medicine

University of Iowa

Modeling the Effects of Hemodynamic Stress on Circulating Tumor Cells using a Syringe and Needle

Benjamin L. Krog

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Molecular Physiology and Biophysics,Carver College of Medicine,Department of Molecular Physiology and Biophysics, Carver College of Medicine

University of Iowa

Modeling the Effects of Hemodynamic Stress on Circulating Tumor Cells using a Syringe and Needle

Department of Molecular Physiology and Biophysics,
Carver College of Medicine,
Department of Molecular Physiology and Biophysics, Carver College of Medicine