Abstract
Cancer cell metastasis is the main cause of death in patients with cancer. Many studies have investigated the biochemical factors that affect metastasis; however, the role of physical factors such as fluid shear stress (FSS) in tumorigenesis and metastasis have been less investigated. Triple-negative breast cancer (TNBC) has a higher incidence of lymph node invasion and distant metastasis than other subtypes of breast cancer. In this study, we investigated the influence of FSS in regulating the malignant behavior of TNBC cells. Our data demonstrate that low FSS promotes cell migration, invasion, and drug resistance, while high FSS has the opposite results; additionally, we found that these phenomena were regulated through focal adhesion kinase (FAK). Using immunohistochemistry staining, we show that FAK levels correlate with the nodal stage and that FAK is a significant independent predictor of overall survival in patients. Altogether, these data implicate FAK as a fluid mechano-sensor that regulates the cell motility induced by FSS and provide a strong rationale for cancer treatments that combine the use of anti-cancer drugs and strategies to modulate tumor interstitial fluid flow.
Highlights
Cancer is the leading cause of death worldwide
We characterized the effect of fluid shear stress (FSS) on triple-negative breast cancer (TNBC) cell morphology
We indicated that downregulation of focal adhesion kinase (FAK) by high FSS is via ubiquitination mediated proteosomal degradation, and other studies have indicated that FSS promotes several protein degradation in endothelial or cancer cells [10,46,47] we supposed that the inhibition of total and phosphor-FAK by high FSS in TNBC cells could be related to protein stability and degradation
Summary
Cancer is the leading cause of death worldwide. Most cancer-related deaths are not caused by the primary tumors, but by metastases. Prior studies have focused mostly on the biochemical factors that affect metastasis formation; the effect of several physical factors on this process has been less investigated. Increasing evidence has indicated that mechanical stress plays an important role in tissue development and maintenance, and in the pathogenesis of several diseases, including cancer [2]. The fluid flow in and around the tumor tissues affects the extracellular gradient of chemokines and growth factors and plays a role in the delivery of anti-cancer drugs [3,4,5]. The influence of flow-induced stress on tumor cell biology and malignancy has been poorly investigated
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