Distant metastasis in cancer patients results from cancer cells escape from a primary tumor and travel through the bloodstream to secondary organ sites. Little is known about how this journey affects the biology of these circulating tumor cells (CTCs). Within the bloodstream, CTCs are exposed to hemodynamic forces which are foreign to cancer cells derived from epithelial organs. It has recently been shown that cancer cell lines from numerous epithelial tissues exhibit an acquired resistance to brief pulses of high level fluid shear stress (FSS) compared to normal or benign epithelial cells. This phenotype reflects signaling through at least several common oncogenic pathways. The objective of this proposal is to elucidate the mechanism(s) underlying FSS-resistance in cancer cells and to gain a greater understanding of how CTCs experience FSS in circulation using a model of the human heart and measuring FSS-resistance in CTCs from a mouse model of prostate cancer metastasis. The central hypothesis of this proposal is that cancer cells in the circulation are exposed to brief pulses of high-level FSS that trigger membrane-cytoskeletal changes which confer resistance to FSS. The rationale for the proposed research is that it will for the first tim elucidate how cancer cells respond to FSS, and how this relates to the ability of CTCs to survive hemodynamic forces.
The specific aims of this proposal are: 1) Determine the mechanisms underlying FSS resistance in cancer cells. Based on our preliminary data, our working hypothesis is that exposure to FSS induces calcium entry through damaged plasma membrane. This triggers plasma membrane repair as well as Rho-dependent modulation of the actin cytoskeleton which renders cells resistant to subsequent exposure to FSS; and 2) Measure the effects of physiologic FSS on cancer cells. Based on our observations on the effects of brief pulses of high level FSS on cancer cells, our working hypothesis is that CTCs also experience these forces in physiologic settings and exhibit FSS resistance. We will employ a device that accurately models the human heart to determine if exposure to brief pulses of high-level shear stress triggers FSS resistance in cancer cells and we will measure FSS resistance in CTCs in blood samples from mice. The contribution of this proposal will be significant because it will begin to elucidate the mechanisms for how cancer cells respond to fluid shear stress and to determine if CTCs exhibit FSS resistance under physiological settings. Elucidating the mechanisms underlying FSS-resistance may have implications for diagnostic approaches, for instance, by using FSS as a means to distinguish benign from malignant cells. Likewise, these studies may inform therapeutic approaches to reduce metastatic potential by interfering with FSS-resistance. The proposed research is conceptually innovative because it challenges the commonly held idea that CTCs are intrinsically fragile and highly subject to destruction from hemodynamic shear forces and technically innovative because we will use a device that recapitulates physiologic shear stress in the human heart to explore the effects of FSS in cancer cells.

Public Health Relevance

The proposed research is relevant to the mission of the NCI because it seeks to discover basic mechanisms underlying how metastatic cancer cells experience and respond to hemodynamic shear stress while they are in the circulation. These studies will be broadly applicable to many types of cancer derived from epithelial organs, which spread via hematogenous metastasis. These studies represent a new avenue of research, because very little is known about how hemodynamic forces influence cancer cell biology; cancer cell resistance to such forces has not been explored before.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Tumor Progression and Metastasis Study Section (TPM)
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Kuhn, Nastaran Z
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University of Iowa
Schools of Medicine
Iowa City
United States
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