Development of Peritoneal Carcinomatosis in Epithelial Ovarian Cancer: A Review

Abstract

Epithelial ovarian cancer (EOC) metastasizes intra-abdominally with often numerous, superficial, small-sized lesions. This so-called peritoneal carcinomatosis is difficult to treat, and peritoneal recurrences are frequently observed, leading to a poor prognosis. Underlying mechanisms of interactions between EOC and peritoneal cells are incompletely understood. This review summarizes and discusses the development of peritoneal carcinomatosis from a cell-biological perspective, focusing on characteristics of EOC and peritoneal cells. We aim to provide insight into how peritoneum facilitates tumor adhesion but limits size of lesions and depth of invasion. The development of peritoneal carcinomatosis is a multistep process that requires adaptations of EOC and peritoneal cells. Mechanisms that enable tumor adhesion and growth involve cadherin restructuring on EOC cells, integrin-mediated adhesion, and mesothelial evasion by mechanical forces driven by integrin-ligand interactions. Clinical trials targeting these mechanisms, however, showed only limited effects. Other factors that inhibit tumor growth and deep invasion are virtually unknown. Future studies are needed to elucidate the exact mechanisms that underlie the development and limited growth of peritoneal carcinomatosis. This review on development of peritoneal carcinomatosis of EOC summarizes the current knowledge and its limitations. Clarification of the stepwise process may inspire future research to investigate new treatment approaches of peritoneal carcinomatosis.

Keywords: epithelial ovarian carcinoma; pathogenesis; peritoneal barrier; peritoneal metastases; peritoneal metastasis; peritoneum.

Figure 1.

Peritoneal carcinomatosis, a condition often present in epithelial ovarian cancer, is characterized by small, white-colored tumor depositions, localized at the parietal (A–C) and visceral (D) peritoneum (arrows). The diaphragm is often involved (A, B), and presence of peritoneal carcinomatosis is generally accompanied by malignant ascites (asterisk).

Figure 2.

Extraperitoneal metastasis. (A) Sister Mary Joseph nodule. (B) Port-site metastasis in the trocar opening after a laparoscopic procedure.

Figure 3.

Schematic illustration of the peritoneum.

Figure 4.

Histopathological images of the peritoneum. (A) H&E staining of normal peritoneum showing mesothelial cells (M) lining the peritoneum and submesothelial stroma (S). Small areas of the mesothelial cells are denuded, due to trauma during surgery or tissue processing. (B) EVG staining showing the peritoneal elastic fibers (E), embedded in the stroma. C–F. H&E and EVG staining of peritoneal metastases show the small-sized depositions of EOC (C), with only superficial invasion of stroma (S) and absence of mesothelial cells in the presence of EOC. Scale bars A and B = 125 μm; C and D = 500 μm; E and F = 1 mm. Abbreviations: EVG, Elastic van Gieson; EOC, epithelial ovarian cancer.

Figure 5.

Development of metastasis of an epithelial malignancy. Metastatic cancer cells detach from a primary epithelial malignancy (1) and grow through an epithelial cell layer (2). Underlying basal lamina and stroma are penetrated by the exfoliated cancer cells (3). When resided in the stroma, cancer cells resist apoptosis and recruit growth factors that promote proliferation and angiogenesis (4). Blood vessels in the proximity of a tumor enable development of metastasis to a distant location. Cancer cells penetrate through the endothelial cell lining the blood vessels (5) and are transferred to secondary regions (6). At a future metastatic location, cancer cells adhere (7) and penetrate (8) the endothelium to develop a new metastasis.

Figure 6.

Development of peritoneal metastasis of epithelial ovarian carcinoma. (1) EOC cells exfoliate from a primary tumor and undergo EMT to acquire an invasive migratory phenotype, which is characterized by a cadherin switch. (2) In the peritoneal fluid, EOC cells form tumor cell clusters via β₁ integrin-fibronectin interactions that prevents anoikis. (3) EOC cells migrate passively within the peritoneal fluid along the peritoneum. To develop a peritoneal metastasis, EOC cells adhere to the mesothelial cells by integrin-mediated and non-integrin–mediated interactions. (4) Once the EOC cells have penetrated the mesothelial cell layer, EOC cells bind to components of the ECM within the stroma of the peritoneum, and an inflammatory response is generated resulting in increased production of pro-inflammatory cytokines. (5) Within the peritoneal stroma, a chemokine gradient is produced. Inflammatory cells are recruited along the gradient toward the EOC cells and contribute further to cancer progression by production of proteases, angiogenic factors, growth factors, and cytokines, which suppress immune responses. (6) To produce a tumor-supportive microenvironment, cancer-associated fibroblasts, which originate from mesothelial cells, produce cytokines and VEGF. Abbreviations: EOC, epithelial ovarian cancer; EMT, epithelial-to-mesenchymal transition; ECM, extracellular matrix; E-cadherin, epithelial cadherin; N-cadherin, neural cadherin; P-cadherin, platelet cadherin; VEGF, vascular endothelial growth factor; VCAM-1 = vascular cell adhesion molecule; ICAM-1 = intercellular cell adhesion molecule; CA125/MUC16 = Cancer Antigen 125/Mucin 16; GnRH = Gonadotropin-releasing hormone; L1CAM = L1 cell adhesion molecule; TNF-α, tissue necrosis factor-α; IFN-γ, interferon-γ; IL-1β, interleukin-1β; IL-6, interleukin-6; SDF, stromal-derived factor; CAF, cancer-associated fibroblasts.