Lipopolysaccharide induces inflammation and facilitates lung metastasis in a breast cancer model via the prostaglandin E2-EP2 pathway

Abstract

Inflammation is a potent promoter of tumor metastasis. The aim of the present study was to explore the function of systemic inflammation in the formation of lung metastasis of breast cancer cells in a mouse model. BALB/c mice were injected intraperitoneally with lipopolysaccharide (LPS) in order to establish an inflammatory animal model and 4T1 murine breast cancer cells were injected through the tail vein to induce lung metastasis. The levels of proinflammatory cytokines were evaluated by ELISA. Metastases on the surface of the lungs were counted and histologically analyzed by hematoxylin and eosin staining. Angiogenesis in the lungs was examined by CD31 immunofluorescence. Mouse pulmonary endothelial cells (MPVECs) were isolated and used to assay endothelial tube formation and determine the protein expression levels of vascular endothelial growth factor (VEGF) in vitro. Serum levels of VEGF and prostaglandin E2 (PGE2), the number and size of metastatic lesions, and the expression levels of cyclooxygenase‑2 were significantly greater in the lungs of LPS‑treated mice, as compared with those in control mice threated with phosphate‑buffered saline. Blood vessel density was also markedly increased in the LPS‑treated mice. These increases were reversed by treatment with celecoxib. In vitro, the protein expression levels of VEGF produced by the PGE2‑treated cells were significantly increased in a concentration‑dependent manner. In addition, the production of VEGF was increased in response to treatment with the PGE2 receptor (EP2) agonist ONO‑AE1‑259‑01; however, this increase was abrogated by treatment with AH6809, an EP2 receptor antagonist. Treatment with PGE2 or VEGF alone promoted the tube formation of MPVECs and this effect was reversed by treatment with celecoxib. These results demonstrated that PGE2 may regulate the release of VEGF by MPVECs through the EP2 receptor pathway and thereby promoted pulmonary angiogenesis and breast cancer metastasis in a mouse model.

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

“…A series of studies of prostaglandin in cancers showed that the subtype of EPs effect in different cancers was variable [5, 6, 31]. A recent study showed that PGE2 induces lung metastasis in breast cancers via EP2 [32]. However, in endometrial cancers, no result of PGE2 functional activation has ever been reported.…”

Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

“…In such a model of continuous LPS stimulation, EndMT might be involved not only in pulmonary fibrosis but also in pathological angiogenesis as is observed in tumor progression (54). Indeed, LPS were reported to induce lung metastasis of breast cancer (31). Thus how EndMT changes according to dose or duration of LPS or with other changes to the mouse model will be an issue to be investigated in the future.…”

Obesity-associated cancer risk: the role of intestinal microbiota in the etiology of the host proinflammatory state

“…Eicosanoids can also indirectly affect cancer growth. For example, PGE 2 induces aromatase expression, which is relevant to survival from postmenopausal breast cancer (39), in addition to the more direct effects of PGE 2 on driving breast cancer growth and metastases (33, 40, 41). Eicosanoids can be measured in tissues, but in epidemiological studies stable metabolites have more often been measured in urine.…”