Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research

Abstract

Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer.

Figure 1. The peritoneum, peritoneal membrane and ascites

a ∣ The peritoneal membrane covers the visceral organs, as well as the abdominal and pelvic cavities, and consists of five layers. The first layer is made up of endothelial cells that line the intravascular space of capillaries. These cells have an extracellular glycocalyx and fixed anionic charge that makes it difficult for large blood plasma proteins, such as albumin, to pass through. Intracellular pores provide transport through this layer. The endothelial cell basement membrane provides the second layer. The interstitial space is the third layer and contains fibroblasts, collagen and hyaluronic acid, and it can block the diffusion of macromolecules before the submesothelial basement membrane (the fourth layer). The final layer consists of mesothelial cells. Bound by tight junctions and secreting surface glycosaminoglycans (hyaluronan) into the abdominal space, mesothelial cells provide an effective anti-adhesive surface and a protective barrier against physical damage. In physiological conditions, the difference in oncotic pressure across the peritoneal membrane (high at the endothelial layer and low at the mesothelial layer) limits capillary fluid filtration and prevents oedema that is due to water reabsorption into the capillaries from the interstitial space. b ∣ In patients with tumours in the abdominal cavity, the cross-sectional area of microvessels lining the peritoneal cavity is increased, and this results in an increased filtration surface for fluid. In addition, malignant ascites has a high protein concentration that is secondary to increased capillary permeability. Inflammatory cytokines and chemokines, as well as reduced lymphatic flow, all contribute to alterations of the peritoneal membrane. These changes decrease the plasma to peritoneal oncotic pressure difference, so the direction of flow of fluid is into the peritoneal cavity, obeying Starling’s hypothesis of capillary haemodynamics. This leads to the build up of pathological volumes of fluid in the peritoneal cavity. c ∣ A computed tomography image of a patient with ovarian cancer showing the accumulation of ascites in the abdomen, leading to the compression of organs and tissues in the abdominal cavity. Image in part c courtesy of N. Tunariu, Royal Marsden Hospital, UK.