Microfluidics is a rising tool used to study the effect of fluid flow on the alteration of cellular behavior. However, those systems have different limitations, such as incapability of generating shear stress as low as physiological values, uneven flow distribution and difficulty in achieving precise control over the shear stress 16. Various in vitro culture systems have been used to mimic the fluidic flow, including parallel plate device 12, 13, rocker plates 12, spinner flasks 14 and rotating wall bioreactors 15. This also highlights some deficiencies in the currently used cell-based screening platforms for new drug discovery and subsequent efficacy testing. However, due to its relative difficulty to manipulate and investigate, a dynamic system with fluid flow has been largely neglected thus far and therefore, CSC phenotypes under flow conditions remain poorly understood. This is due mainly to technical limitations in studying CSCs in a sensitive, representative manner in a clinically relevant setting.Р”В®merging evidence shows that mechanical stimuli, including pressure, stretching and shear stress, can modulate the morphology, expression of biomarkers and aggressiveness of tumor cells 9, 10, 11. However, the key signals regulating the formation and expansion of CSCs remain elusive. Thus, it is conceivable that tumor recurrence is probably due to the fact that standard chemotherapeutic regimens fail to kill CSCs which can regenerate the entire tumor 8.

Unlike bulk tumor cells, CSCs are highly tumorigenic and drug resistant and possess self-renewal capacity. CSCs have been discovered in various cancers, including ovarian cancer they have been shown through identifying Hoechst 33342 side population cells or staining for stem cell-specific markers, as well as through enrichment of suspension cultures as spheroids that most closely mimic the advanced stage of ovarian carcinoma present in malignant ascites 3, 4, 5, 6, 7. The discovery of cancer stem cells (CSCs) has advanced our understanding of tumorigenesis and chemoresistance and may provide novel targets for cancer therapy. Unravelling the molecular mechanisms contributing to this resistance is critically important. This high degree of inherent and acquired chemoresistance makes treating ovarian cancer particularly challenging (5-year survival rate <25%) 2. Despite initial response, over 85% of advanced ovarian cancer patients experience relapse and succumb to the disease. Most of the ovarian cancer patients are diagnosed at an advanced stage (stage III or IV) characterized by large volume of ascites formation and widespread peritoneal dissemination. Ovarian cancer has the highest mortality of all gynecological cancers worldwide 1.

Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt and multidrug transporter activation in shear stress-induced CSC enrichment. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. However, little is known about key signals regulating the formation and expansion of CSCs. An exciting approach is the eradication of cancer stem cells (CSCs).

One of greatest challenges to the successful treatment of cancer is drug resistance.

Acad 2016 shear tool