Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

Abstract

Perspective: The role of mechanobiology in the etiology of brain metastasis APL Bioengineering 2, 031801 (2018) Ovarian cancer remains a deadly diagnosis with an 85% recurrence rate and a 5-year survival rate of only 46%. The poor outlook of this disease has improved little over the past 50 years owing to the lack of early detection, chemoresistance and the complex tumor microenvironment. Within the peritoneal cavity, the presence of ascites stimulates ovarian tumors with shear stresses. The stiff environment found within the tumor extracellular matrix and the peritoneal membrane are also implicated in the metastatic potential and epithelial to mesenchymal transition (EMT) of ovarian cancer. Though these mechanical cues remain highly relevant to the understanding and treatment of ovarian cancers, our current knowledge of their biological processes and their clinical relevance is deeply lacking. Seminal studies on ovarian cancer mechanotransduction have demonstrated close ties between mechanotransduction and ovarian cancer chemoresistance, EMT, enhanced cancer stem cell populations, and metastasis. This review summarizes our current understanding of ovarian cancer mechanotransduction and the gaps in knowledge that exist. Future investigations on ovarian cancer mechanotransduction will greatly improve clinical outcomes via systematic studies that determine shear stress magnitude and its influence on ovarian cancer progression, metastasis, and treatment.

Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress

“…Approximately one-third of all ovarian cancer patients will develop ascites, but this number can be as high as nearly 90% [99] in patients with advanced-stage disease (stages III or IV). The presence and progression of ascites are associated with grim survival statistics, a decreased quality of life, and may have predictive value for malignant ovarian tumors [3,5,11,[14][15][16][17]26,31,[99][100][101][102]. The predictive value of ascites remains a source of debate, as is the case with most clinical and biological markers for this challenging disease [98,[103][104][105].…”

“…The cellular components of ascites include tumor and stromal cells present as single cells or as tumor clusters/spheroids. A complex milieu of proteins, cytokines, metabolites, and exosomes, among other factors, constitute the acellular components of ascitic fluid [3,5,11,[14][15][16][17]26,31,[99][100][101][102]. Interaction with ascites has been shown to modulate the molecular phenotype of ovarian cancer cells and to contribute to tumor heterogeneity [11,16,17,31,106].…”

“…Flow-induced shear stress has been shown to induce changes in the morphologic, genetic, and protein profiles of cancers, including ovarian cancer [18][19][20][21][22][23][24][25][26]. Previous computational simulations of gastrointestinal models estimated flow-induced shear stress in the peritoneum in the range of 0.14 dyne/cm 2 to 11 dyne/cm 2 [108].…”

“…These effects by ascites on ovarian tumors have largely been studied in the context of the soluble factors (e.g., cytokines and metabolites) and cellular components (e.g., tumor cells and stromal cells) that are commonly found in ascites. In addition to providing a cell-and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress, such as flow-induced shear stress, on tumors [18][19][20][21][22][23][24][25][26]. Natural currents of ascitic fluid result, in part, from organ mobility, changes in negative subdiaphragmatic pressure, gravity, and recesses formed by Ovarian cancer disseminates as individual cells or cell-clusters that exfoliate from the primary tumor and spread via transcoelomic, lymphatic, or hematogenous routes to distant sites [3][4][5][6][7][8][9][10].…”

“…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]. These effects by ascites on ovarian tumors have largely been Fluid stress has been shown to influence tumor migration and invasion and to induce changes in the morphologic, genetic, and protein expression profiles of cancers, including ovarian cancer [18][19][20][21][22][23][24][25][26]. We have previously shown a post-translational upregulation and activation of the epidermal growth factor receptor (EGFR) in a 3D perfusion model for ovarian cancer [25].…”