Abstract B64: Self-organization of ovarian cancer cells into multicellular irregular aggregates and highly organized spheroids

Abstract

Abstract Most women diagnosed with ovarian cancer (OvCa) are at an advanced stage with accumulation of peritoneal fluid (ascites) containing multicellular clusters. Despite all macroscopic disease is resected and any remaining microscopic disease is subjected to platinum-taxane chemotherapy, most patients, after a period of disease dormancy, relapse and die as a consequence of tumor progression. OvCa recurs within the peritoneal cavity with the accumulation of ascitic fluid carrying multicellular clusters, in association with the formation of numerous nodular growths in the peritoneal wall, resembling the disease when first diagnosed. Therefore, it is critical to determine: i) if the ability of OvCa cells to self-assemble into multicellular structures within ascites represents an adaptive or passive biological phenomenon; and ii) which is its contribution to disease progression. In this work we provide evidences that human serous OvCa cells derived from treatment-resistant relapsed disease, while growing as an adherent monolayer, spontaneously self-assemble into multicellular foci that float away off the adherent component of the culture. The floating phenotype is comprised of two types of structures: 1) irregular cellular clusters; and 2) organized spheroids with blastocyst-like morphology or cystic embryoid bodies (EBs). Within each multicellular structure cells gather differently as evidenced by the distribution pattern of the cell junction adhesion molecule E-cadherin. DNA synthesis occurrs in both types of non-adherent multicellular aggregates, yet at a remarkable low rate in spheroids. Both structures in suspension are composed of live cells with no morphological features of apoptosis, indicating their resistance to anoikis. The blastocyst-like or cystic EBs spheroids of OvCa cells have the capacity to recreate the entire culture phenotype when placed in a new culture dish; the spheroids adhere upon transference and develop foci that grow upright irregular aggregates and more organized spheroids, ultimately leading to the generation of new non-adherent multicellular structures. The floating structures include clusters of cells expressing the cancer initiating antigen CD133, and cells producing fibronectin, an extracellular matrix component. In summary, this study characterized an in vitro model of recurrent, treatment-resistant serous OvCa cells with intrinsic ability to gather in two types of clusters that survive in an anchorage-independent manner'a hallmark of transformation and a critical feature of metastatic disease. Unveiling the relevance of OvCa self-assembly in suspension and understanding the mechanisms critically involved in their formation, viability, metastatic capabilities, and growth should provide clues as to how to intercept disease progression. Citation Format: Alicia A. Goyeneche. Self-organization of ovarian cancer cells into multicellular irregular aggregates and highly organized spheroids. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B64.