More than one third of ovarian cancer patients present with ascites at diagnosis, and almost all have ascites at recurrence. The presence of ascites correlates with the peritoneal spread of ovarian cancer and is associated with poor disease prognosis. Malignant ascites acts as a reservoir of a complex mixture of soluble factors and cellular components which provide a pro-inflammatory and tumor-promoting microenvironment for the tumor cells. Subpopulations of these tumor cells exhibit cancer stem-like phenotypes, possess enhanced resistance to therapies and the capacity for distal metastatic spread and recurrent disease. Thus, ascites-derived malignant cells and the ascites microenvironment represent a major source of morbidity and mortality for ovarian cancer patients. This review focuses on recent advances in our understanding of the molecular, cellular, and functional characteristics of the cellular populations within ascites and discusses their contributions to ovarian cancer metastasis, chemoresistance, and recurrence. We highlight in particular recent translational findings which have used primary ascites-derived tumor cells as a tool to understand the pathogenesis of the disease, yielding new insights and targets for therapeutic manipulation.

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Tumor cells in ascites are a major source of disease recurrence in ovarian cancer patients. In an attempt to identify and profile the population of ascites cells obtained from ovarian cancer patients, a novel method was developed to separate adherent (AD) and non-adherent (NAD) cells in culture. Twenty-five patients were recruited to this study; 11 chemonaive (CN) and 14 chemoresistant (CR). AD cells from both CN and CR patients exhibited mesenchymal morphology with an antigen profile of mesenchymal stem cells and fibroblasts. Conversely, NAD cells had an epithelial morphology with enhanced expression of cancer antigen 125 (CA125), epithelial cell adhesion molecule (EpCAM) and cytokeratin 7. NAD cells developed infiltrating tumors and ascites within 12–14 weeks after intraperitoneal (i.p.) injections into nude mice, whereas AD cells remained non-tumorigenic for up to 20 weeks. Subsequent comparison of selective epithelial, mesenchymal and cancer stem cell (CSC) markers between AD and NAD populations of CN and CR patients demonstrated an enhanced trend in mRNA expression of E-cadherin, EpCAM, STAT3 and Oct4 in the NAD population of CR patients. A similar trend of enhanced mRNA expression of CD44, MMP9 and Oct4 was observed in the AD population of CR patients. Hence, using a novel purification method we demonstrate for the first time a distinct separation of ascites cells into epithelial tumorigenic and mesenchymal non-tumorigenic populations. We also demonstrate that cells from the ascites of CR patients are predominantly epithelial and show a trend towards increased mRNA expression of genes associated with CSCs, compared to cells isolated from the ascites of CN patients. As the tumor cells in the ascites of ovarian cancer patients play a dominant role in disease recurrence, a thorough understanding of the biology of the ascites microenvironment from CR and CN patients is essential for effective therapeutic interventions.

The type III transforming growth factor ␤ (TGF␤) receptor (T␤RIII) binds both TGF␤ and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of T␤RIII signaling in vivo is not known. In this study, we have sought to determine the role of T␤RIII during development. We identified the predominant expression sites of ⌻␤RIII mRNA as liver and heart during midgestation and have disrupted the murine T␤RIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in ⌻␤RIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that T␤RIII is required during murine somatic development. To assess the effects of the absence of T␤RIII on the function of its ligands, primary fibroblasts were generated from T␤RIII-null and wild-type embryos. Our results indicate that T␤RIII deficiency differentially affects the activities of TGF␤ ligands. Notably, T␤RIII-null cells exhibited significantly reduced sensitivity to TGF␤2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that T␤RIII is an important modulator of TGF␤2 function in embryonic fibroblasts and that reduced sensitivity to TGF␤2 may underlie aspects of the T␤RIII mutant phenotype.Members of the transforming growth factor ␤ (TGF␤) family are potent regulators of multiple cellular functions, including cell proliferation, differentiation, migration, and death (35, 64). As such, the TGF␤s are critical regulators of the growth and morphogenesis of a variety of tissues. Three TGF␤ isoforms (TGF␤1 to -3) have been described in mammals and are encoded by distinct genes (36). Although the three ligands have similar biological activities in many in vitro assays, null mutations in the three genes result in mice with distinct phenotypes, suggesting that each ligand has a unique role during murine somatic development (14,42,50). In mammalian cells, the diverse actions of the TGF␤s are mediated by two distinct type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively), which are expressed on most cell types and tissues (35). T␤RI and T␤RII can form a latent receptor complex, and ligand binding is required for the activation of the receptor complex (65). Upon TGF␤ binding, the receptors rotate relatively within the complex (65, 66), resulting in phosphorylation and activation of T␤RI by the constitutively active and autophosphorylated T␤RII (62). The activated T␤RI then directly signals to downstream intracellular substrates, e.g., Smads (21, 61).Many other cell surface receptors have been identified (64). Among them is the type III TGF␤ receptor T␤RIII, which binds to all three TGF␤s (32). In contrast to the type I and II receptors, T␤RIII, also known as betaglycan, appears dispensable for TGF␤-mediated signal transduction since most cells that lack functional T␤RIII still respond to TGF␤ (8). The murine form of T␤RIII is an 850-...