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Normal saline remodels the omentum and stimulates its receptivity for transcoelomic metastasis
Hironari Akasaka, … , Ernst Lengyel, Honami Naora
Hironari Akasaka, … , Ernst Lengyel, Honami Naora
Published June 22, 2023
Citation Information: JCI Insight. 2023;8(12):e167336. https://doi.org/10.1172/jci.insight.167336.
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Research Article Oncology

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

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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 4

Normal saline promotes omental neoangiogenesis and cancer cell implantation through increasing CX3CR1+ SPM-like cells.

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Normal saline promotes omental neoangiogenesis and cancer cell implantat...
(A–D) Cx3cr1+/GFP and Cx3cr1GFP/GFP mice were left untreated or administered normal saline (n = 5 per group). At 7 days thereafter, omental tissues were evaluated for CD45 staining (A), numbers of CD11bintF4/80loMHCII+ (SPM-like) cells (B), CD31 staining (C), and microvessel density (D). Scale bar in A and C: 200 μm. (E) CX3CR1+ SPM-like cells were sorted from omenta of untreated C57BL/6 mice and at day 1 following saline administration (n = 5 per group). Lysates of pooled cells of each group were screened on antibody arrays. Shown are proteins with > 1.5-fold higher levels in saline-treated mice relative to untreated mice. Bars represent the averages of 2 replicates. Asterisks indicate proangiogenic proteins. (F and G) CX3CR1+ SPM-like cells were sorted from omenta of untreated C57BL/6 mice and at 1 hour following saline administration (n = 6 per group) and were stained for NF-κB p65. (F) Representative images of cells. Scale bar: 20 μm. (G) Percentages of cells with nuclear NF-κB p65. For each mouse, a minimum of 300 cells were evaluated. (H and I) Cx3cr1+/GFP and Cx3cr1GFP/GFP mice were left untreated or administered saline (n = 6 per group). At 7 days thereafter, all groups were inoculated i.p. with ID8 cells that express red fluorescent protein (RFP). Omental colonization was evaluated at 7 days following inoculation. (H) Representative images of tissues. Scale bar: 200 μm. (I) Tumor foci, expressed as the percentage of area within each tissue. For each mouse, RFP fluorescence was evaluated in 3–5 random and independent 40× microscopic fields. Age-matched adult female mice were used in A–I. **P < 0.01, ***P < 0.001, ****P < 0.0001, by Tukey’s multiple comparisons test in B, D, and I, by unpaired 2-tailed Student’s t-test in G.

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