RESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/patología , Mama/patología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Estrés Mecánico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fenómenos Biomecánicos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Transducción de Señal/efectos de los fármacos , Microtomografía por Rayos X , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The enhancement of wound healing has been a goal of medical practitioners for thousands of years. The development of chronic, non-healing wounds is a persistent medical problem that drives patient morbidity and increases healthcare costs. A key aspect of many non-healing wounds is the reduced presence of vessel growth through the process of angiogenesis. This review surveys the creation of new treatments for healing cutaneous wounds through therapeutic angiogenesis. In particular, we discuss the challenges and advancement that have been made in delivering biologic, pharmaceutical and cell-based therapies as enhancers of wound vascularity and healing.