Despite the relatively low incidence and decades of research into diagnosis and treatment, ovarian cancer is still the 5th leading cause of death due to cancer for women in the USA. With a current survival rate of only 45% (2004-2010), understanding the mechanisms of ovarian cancer development/spread will be integral to finding the solutions. In this study, we examined 9 ovarian cancer cell lines in an anchorage-independent culture system in order to evaluate 3-D spheroids as an in vitro tool for the study of ovarian cancer. Using microarray profiling (iSCAN) of miR and mRNA expression we classified the cell lines based on their primary response in an anchorage-independent culture environment. The array results implicated the EMT/MET and hypoxia pathways, among others, as integral in the compaction of cell aggregates into dense spheroids. Of interest were vimentin and stanniocalcin 2 (STC2). Both were shown to increase significantly on formation of compact spheroids, when compared to cell lines with loose aggregates and monolayer cultures. Vimentin expression and subsequent knock-down (KD) studies, in the HEY cell line, confirmed it’s central role in forming and maintaining a structured spheroid. Unexpectedly, KD of STC2 resulted in spheroids that were smaller and/or more compact. Furthermore, KD of vimentin altered the expression level of STC2 as well. We indicate that there is a balance between the hypoxic environment, created during modelling of the 3-D structure, and compaction events in anchorage-independent growth. Furthermore, maintenance of this state requires cooperation of effectors involved in the cell-cell adhesion (vimentin) and hypoxia/angiogenesis (STC2) pathways. Most likely, STC2 is co-stimulated in response to the events associated with the creation of a compact cell aggregate as a way to maintain a reasonable level of permeability and stimulate angiogenesis when conditions permit.