Spontaneous spheroid budding from monolayers: a potential contribution to ovarian cancer dissemination

Abstract

SummaryOvarian cancer is the most lethal gynaecologic cancer, in large part because of its early dissemination and rapid development of chemotherapy resistance. Spheroids are clusters of tumor cells found in the peritoneal fluid of patients that are thought to promote this dissemination. Current models suggest that spheroids form by aggregation of single tumor cells shed from the primary tumor. Here, we demonstrate that spheroids can also form by budding directly as adherent clusters from a monolayer. Formation of budded spheroids correlated with expression of vimentin and lack of cortical E-cadherin. We also found that compared to cells grown in monolayers, cells grown as spheroids acquired progressive resistance to the chemotherapy drugs Paclitaxel and Cisplatin. This resistance could be completely reversed by dissociating the spheroids. Our observations highlight a previously unappreciated mode of spheroid formation that might have implications for tumor dissemination and chemotherapy resistance in patients, and suggest that this resistance might be reversed by spheroid dissociation.

Tumor suppressor candidate 3 (TUSC3) prevents the epithelial-to-mesenchymal transition and inhibits tumor growth by modulating the endoplasmic reticulum stress response in ovarian cancer cells

“…The EMT phenotype is also associated with the formation of multicellular spheroids. Recently, Pease et al . reported spontaneous formation of 3D aggregates budding from monolayers of ovarian cancer cells.…”

“…9,10 The EMT phenotype is also associated with the formation of multicellular spheroids. Recently, Pease et al 52 reported spontaneous formation of 3D aggregates budding from monolayers of ovarian cancer cells. Interestingly, these buds lacked cortical E-Cadherin, could effectively detach from the monolayer, and survived even in the presence of commonly used cytotoxic drugs.…”

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

“…Formation of spheroids is another characteristic feature of ovarian cancer metastasis (37). Spheroids provide an evolutionary advantage in tumor progression as they are less sensitive to chemotherapy due to up-regulation of B-cell leukemia-xL (BCL-xL) (38).…”

“…Spheroids provide an evolutionary advantage in tumor progression as they are less sensitive to chemotherapy due to up-regulation of B-cell leukemia-xL (BCL-xL) (38). In addition, they exhibit pronounced capacity to adhere to components of the ECM and mesothelial cells (37). Tumor cells in spheroids are also protected against antitumoral immune effector cells (29,30 (30).…”

Polyploid monolayer Ishikawa endometrial cells form unicellular hollow spheroids capable of migration

“…As Achilli et al (2012) recently described, there are at least 7 other culturing conditions that will result in the formation of spheroids by lessening contact between cells and surfaces such as the plastic surface of petri dishes. Furthermore, and relevant to our discussion, there is at least one paper showing that ovarian cancer cells in a monolayer can give rise to multicellular solid spheroids spontaneously and that these are released into the medium following a period of being tethered to the monolayer that produced them (Pease et al 2012).…”