Abstract
A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress.
Highlights
Advanced-stage epithelial ovarian cancer is the leading cause of death from gynecologic malignancies in the United States, with a five-year survival rate of only 30% [1], a grim statistic that has remained unchanged for decades
Harmless NIR light can be spatially confined and delivered through fiber optics and balloons to the peritoneum and areas of resection to activate photosensitizers [62,63,64,65], giving PIT the advantage of selectivity to the tumor-invaded peritoneum. Building on these and other efforts, we investigate here, for the first time, the influence of flow-induced shear stress on carboplatin resistance and the activity of the EGFR, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), extracellular signal-regulated kinase (ERK) pathway in a 3D perfusion model for ovarian cancer
The perfusion model previously used to assess the effect of flow-induced shear stress on the genetic, molecular, and morphologic features of ovarian cancer in 3D culture over 7 days [25] was modified to evaluate response to carboplatin treatment and PIT in the present study
Summary
Advanced-stage epithelial ovarian cancer is the leading cause of death from gynecologic malignancies in the United States, with a five-year survival rate of only 30% [1], a grim statistic that has remained unchanged for decades. Studies have shown that ascites contribute to tumor heterogeneity, modulate the expression of integrins, and alter the activity of matrix-degrading enzymes in ovarian cancer [5,11,15,16,17]. Harmless NIR light can be spatially confined and delivered through fiber optics and balloons to the peritoneum and areas of resection to activate photosensitizers [62,63,64,65], giving PIT the advantage of selectivity to the tumor-invaded peritoneum Building on these and other efforts, we investigate here, for the first time, the influence of flow-induced shear stress on carboplatin resistance and the activity of the EGFR, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), extracellular signal-regulated kinase (ERK) pathway in a 3D perfusion model for ovarian cancer. A low-dose PIT approach is leveraged to target EGFR overexpression in tumors grown under flow-induced shear stress
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