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Physical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

 

Abstract Photocoagulation of blood vessels offers unambiguous advantages to current radiofrequency approaches considering the high specificity of blood absorption at available laser wavelengths (e.g., 532 nm and 1.064 µm). Successful treatment of pediatric vascular lesions, such as port-wine stains requiring microvascular hemostasis, has been documented. Although laser treatments have been successful in smaller diameter blood vessels, photocoagulation of larger sized vessels is less effective. The hypothesis for this study is that a primary limitation in laser coagulation of large diameter blood vessels (500–1000 µm) originates from shear stress gradients associated with higher flow velocities along with temperature-dependent viscosity changes. Laser (1.07 µm) coagulation of blood vessels was tested in the chicken chorio-allantoic membrane (CAM). A finite element model is developed that includes hypothetical limitations in laser coagulation during irradiation. A protocol to specify laser dosimetry is derived from OCT imaging and angiography observations as well as finite element model results. Laser dosimetry is applied in the CAM model to test the experimental hypothesis that blood shear stress and flow velocity are important parameters for laser coagulation and hemostasis of large diameter blood vessels (500–1000 µm). Our experimental results suggest that shear stress and flow velocity are fundamental in the coagulation of large diameter blood vessels (500–1000 µm). Laser dosimetry is proposed and demonstrated for successful coagulation and hemostasis of large diameter CAM blood vessels. 

Our experience managing conflicting needs for a summer Research Experience for Undergraduate program.