Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response

Abstract

Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.

Keywords: chemoresistance; epithelial ovarian cancer; epithelial to mesenchymal transition; flow-induced shear stress; malignant ascites; mechanical stress; photodynamic therapy; transcoelomic metastases; tumor heterogeneity; tumor microenvironment.

Figure 1

Malignant Ascites in the Dissemination and Progression of Ovarian Cancer. (A) Malignant ascites contributes to intraperitoneal tumor dissemination. Tumor cells detach from the primary tumor site as individual tumor cells or as tumor cell clusters, which can travel via currents of ascitic fluid to other intraperitoneal sites and create secondary cancer sites (transcoelomic route). (B) Ex vivo analysis of patient-derived ascites includes separation of cells using flow cytometry, RNA extraction, and metabolomic or proteomic analysis. In vitro cell line-based models of flow-induced shear stress reveal modulation of markers associated with aggressive disease. (C) Summary of key findings demonstrate increased pro-survival/attenuated anti-death pathways, enhanced metastatic potential and increased resistance to chemotherapy due to malignant ascites and flow-induced shear stress.

Figure 2

Illustration of Heterogeneity in Ovarian Cancer. (A) Contributing tissues and mutated or altered pathways in both type I and type II tumors are illustrated along with various subtypes included in each tumor type. Since HGSOC, a type II tumor, is the focus of this review, the frequency of mutated/altered pathways in type II tumors are noted as percentages, but the frequency of mutated/altered pathways in type I tumors has been omitted. (B) The tumor microenvironment also contributes to intertumoral heterogeneity via ECM remodeling through increased production of collagen, promotion of tumor cell cluster formation and adhesion to secondary intraperitoneal sites, increased angiogenesis through neovascularization, and immune evasion through the involvement of T_regs, NK cells, and MDSCs. (C) The presence of malignant ascites is more frequently associated with type II tumors than type I tumors, and ascites contributes to a tumor-promoting microenvironment through acellular, cellular, and biophysical cues. Acellular factors, including cytokines, growth factors, and integrins, present in the ascites contribute to shaping the tumor microenvironment through enhanced tumor cell proliferation, dissemination, and colonization of distant sites. Cellular components of ascites, which include macrophages, fibroblasts, CAFs, mesothelial cells, MDSCs, individual tumor cells, and tumor cell spheroids, assist with immune evasion and ECM remodeling. Mechanical effects of ascites, notably flow-induced shear stress and interstitial fluid pressure, contribute to a tumor-promoting microenvironment through induction of EMT and increased expression of survival pathways that are indicative of aggressive and metastatic phenotypes, including chemoresistance.