Normal saline remodels the omentum and stimulates its receptivity for transcoelomic metastasis

Abstract

The omentum contains immune cell structures called milky spots that are niches for transcoelomic metastasis. It is difficult to remove the omentum completely, and there are no effective strategies to minimize the risk of colonization of preserved omental tissues by cancer cells that circulate in the peritoneal fluid. Normal saline is commonly administered into the peritoneal cavity for diagnostic and intraoperative lavage. Here we show that normal saline, when administered into the peritoneal cavity of mice, is prominently absorbed by the omentum, exfoliates its mesothelium, and induces expression of CX3CL1, the ligand for CX3CR1, within and surrounding the omental vasculature. Studies using CX3CR1-competent and CX3CR1-deficient mice showed that the predominant response in the omentum following saline administration is an accumulation of CX3CR1 + monocytes/macrophages that expand milky spots and promote neoangiogenesis within these niches. Moreover, saline administration promoted the implantation of cancer cells of ovarian and colorectal origin onto the omentum. By contrast, these deleterious effects were not observed following i.p. administration of lactated Ringer’s solution. Our findings suggest that normal saline stimulates the receptivity of the omentum for cancer cells and that the risk of colonization can be minimized by using a biocompatible crystalloid for lavage procedures.

Revisiting the Use of Normal Saline for Peritoneal Washing in Ovarian Cancer

“…It has been commonly thought that mesothelial cells are stripped by peritoneal washing due to shear stress from the procedure [41,42]. However, in a recent study [33], we found that exposure to normal saline downregulates the tight junction protein zonula occludens-1 (ZO-1) in mesothelial cells, causing these cells to detach (Table 2). A study of rats that underwent laparotomy found that peritoneal washing with normal saline promotes the formation of adhesions [35] (Table 2).…”

“…Decrease in pH [33,34] Mesothelial cell damage • Exfoliation of mesothelial cells; • Formation of peritoneal adhesions.…”

“…Loss of cell adhesion [33] Induction of oxidative stress [36] Impairment of fibrinolytic properties [34,36]…”

“…Because of the absorptive ability of the omentum and its proclivity for transcoelomic metastasis, agents that are administered into the peritoneal cavity need to be evaluated for their impact on the omental microenvironment and for potentially stimulatory effects on metastasis. In a recent study using mouse models [33], we identified that the omentum has a prodigious ability to absorb normal saline administered into the peritoneal cavity and sustains significantly more mesothelial cell exfoliation than other peritoneal fat tissues. Notably, we found that the administration of normal saline stimulates the implantation of ovarian cancer cells onto the omentum through a series of remodeling events that is initiated by mesothelial cell exfoliation.…”

“…CX3CL1 was found to be predominantly expressed as a membrane-bound protein in endothelial cells, and its induction caused monocytes/macrophages that express the cognate receptor C-X3-C motif chemokine receptor 1 (CX3CR1) to accumulate and persist until the omental mesothelium had repaired (Figure 3). Studies using genetically modified mice that express or lack functional CX3CR1 revealed that CX3CR1+ monocytes/macrophages promote the formation of tumor implants on the omentum following the administration of normal saline by stimulating neoangiogenesis [33] (Figure 3).…”