Normal saline remodels the omentum and stimulates its receptivity for transcoelomic metastasis
Hironari Akasaka, WonJae Lee, Song Yi Ko, Ernst Lengyel, Honami Naora
Hironari Akasaka, WonJae Lee, Song Yi Ko, Ernst Lengyel, Honami Naora
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Research Article Oncology

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.

Authors

Hironari Akasaka, WonJae Lee, Song Yi Ko, Ernst Lengyel, Honami Naora

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Figure 6

LRS is less deleterious to mesothelial integrity than normal saline.

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LRS is less deleterious to mesothelial integrity than normal saline. (A ...
(A and B) In vivo analysis of mesothelial cell exfoliation. WT1+ cells were evaluated in omental tissues of untreated mice and at day 1 following i.p. administration of normal saline or LRS at the same dosage (12.5 mL/kg) (n = 6 per group). Adult female C57BL/6 mice were used. (A) Representative images of WT1 staining. Scale bar: 200 μm. (B) Abundance of WT1+ cells, expressed as the percentage of area within omental tissue. Data of untreated and saline-treated groups is duplicated in Figure 1E. (C and D) Ex vivo analysis of mesothelial cell exfoliation. (C) Whole naive omental tissues of adult female C57BL/6 mice were excised and incubated in 2.0 mL of saline or LRS for 1 hour with shaking and in parallel or were left untreated (n = 3 per group). Mesothelial cells that were retained in tissues were quantified by flow cytometric analysis of the CD45–PDPN+CD140a– population (Supplemental Figure 2B). (D) Numbers of retained CD45–PDPN+CD140a– cells per omental fat band. (E–G) In vitro analysis of mesothelial cell exfoliation. Human omental mesothelial cells were plated in plastic or Matrigel-coated 24-well plates and then incubated in 0.5 mL of saline or LRS for the indicated times. Cells that remained attached were detected by crystal violet staining (E) and quantified by measuring absorbance (F). Data of 3 independent experiments is shown in F. (G) ZO-1 staining in untreated and treated cells cultured on plastic chamber slides. Scale bar: 20 μm. Shown are representative images of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by Dunnett’s multiple comparisons test compared with no lavage in B and D and by Tukey’s multiple comparisons test in F.