P-Cadherin Promotes Ovarian Cancer Dissemination Through Tumor Cell Aggregation and Tumor–Peritoneum Interactions

Abstract

More than 60% of patients who are diagnosed with epithelial ovarian cancer (EOC) present with extensive peritoneal carcinomatosis. EOC cells typically disseminate by shedding into the peritoneal fluid where they survive as multi-cellular aggregates and then implant onto peritoneal surfaces. However, the mechanism that facilitates aggregation and implantation of EOC cells is poorly understood. The cell adhesion molecule P-cadherin (CDH3) has been reported to be induced during early progression of EOC and to promote tumor cell migration. In this study, P-cadherin not only promoted migration of EOC cells, but also facilitated the assembly of floating EOC cells into multi-cellular aggregates and inhibited anoikis in vitro. Furthermore, inhibiting P-cadherin by shRNAs or a neutralizing antibody prevented EOC cells from attaching to peritoneal mesothelial cells in vitro. In mouse intraperitoneal xenograft models of EOC, inhibition of P-cadherin decreased the aggregation and survival of floating tumor cells in ascites and reduced the number of tumor implants on peritoneal surfaces. These findings indicate that P-cadherin promotes intraperitoneal dissemination of EOC by facilitating tumor cell aggregation and tumor-peritoneum interactions in addition to promoting tumor cell migration. Implications: Inhibiting P-cadherin blocks multiple, key steps of EOC progression and has therapeutic potential.

Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation

“…This suggests that other proteins may also be involved. Other cadherins, such as Nand P-cadherin and other desmosomal adhesion proteins (such as DSG1, DSG3, DSG4, DSC1 and DSC3), might take part in this process as their activities are associated with cancer development (1,6,22,30,40). Their involvement requires further investigation.…”

“…Metastatic dissemination is associated with deregulation of numerous cell processes, including the ability of tumor cells to aggregate (1). Both proand anti-aggregation forces contribute to promoting cancer dissemination: loss of cohesion forces in the primary tumor allows individual cancer cells or small groups of cells to escape into the lymphatic and circulatory systems (2), whereas the increased cellcell adhesiveness of metastatic cells allows them to form multicellular homotypic aggregates, which have an increased chance of survival once detached from the primary tumor (3).…”

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

“…CS is a hallmark of EMT [75], the process by which epithelial cells lose their characteristic polarity, disassemble cell junctions, and become more migratory as a precursor to invasion and metastasis (they acquire properties analogous to mesenchymal cells) [19,24,60,[76][77][78][79][80][81]. In this setting, CS typically describes a process where the normal expression of E-cadherin is replaced by the abnormal expression of N-cadherin, or where N-cadherin expression is increased and E-cadherin levels remain unchanged [19,60,75].…”

Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)

“…Numerous studies have highlighted the ability of spheroids to acquire chemoresistant, and stem-like properties, both of which have major implications for disease outcome (6,11). Thus far, it is believed that interactions between various cell adhesion molecules and extracellular matrix components contribute to the formation of MCAs, including integrins, fibronectin, and cadherins (5,7,8,12). Interestingly, studies have also shown that gene and protein expression can differ between cancer cells grown in monolayers versus those within multicellular aggregates (11,13).…”