Prostanoid induces premetastatic niche in regional lymph nodes
Fumihiro Ogawa, … , Shuh Narumiya, Masataka Majima
Fumihiro Ogawa, … , Shuh Narumiya, Masataka Majima
Published October 1, 2014
Citation Information: J Clin Invest. 2014;124(11):4882-4894. https://doi.org/10.1172/JCI73530.
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Research Article Oncology

Prostanoid induces premetastatic niche in regional lymph nodes

Abstract

The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2–derived prostaglandin E2 (PGE2) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell–derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE2 receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. Compared with WT CD11c+ DCs, injection of EP3-deficient CD11c+ DCs dramatically reduced accumulation of SDF-1+CD11c+ DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, which may influence the fate of metastasized tumor cells, was also COX-2/EP3–dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3–dependent induction of SDF-1 and suggest that inhibition of this signaling axis may be an effective strategy to suppress premetastatic niche formation and LNM.

Authors

Fumihiro Ogawa, Hideki Amano, Koji Eshima, Yoshiya Ito, Yoshio Matsui, Kanako Hosono, Hidero Kitasato, Akira Iyoda, Kazuya Iwabuchi, Yuji Kumagai, Yukitoshi Satoh, Shuh Narumiya, Masataka Majima

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Figure 5

COX-2–derived PGE2-EP3 signaling induces LNM by facilitating the accumulation of Treg cells.

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COX-2–derived PGE2-EP3 signaling induces LNM by facilitating the accumul...
(A) Localization of FOXP3-positive cells in the subcapsular regions in regional lymph nodes at 7 days. Images are typical results from each group. Scale bar: 50 μm. (B) Temporal changes in the FOXP3-positive cell population in the regional lymph nodes. Vehicle, n = 15; celecoxib, n = 15; AMD3100, n = 10; Ep3 KO, n = 5. *P < 0.0001 (ANOVA). Student’s t test was used to evaluate significant differences at days 3, 5, and 7 (P < 0.05). (C) CD11c/TGF-β1 immunofluorescence images in regional lymph nodes from WT mice and Ep3 KO mice at 10 days. The number of CD11c/TGF-β1–double positive cells was markedly reduced in Ep3 KO mice compared with that in WT mice. Scale bars: 50 μm. (D) TGF-β1 secretion by WT DCs and Ep3 KO DCs stimulated with an EP3 agonist (ONO-AE-248, 0.01 nM). The amount of immunoreactive TGF-β1 in the culture medium was determined by ELISA. n = 6. *P < 0.05 (Student’s t test). (E) Temporal changes in Tgfb1 expression in the regional lymph nodes after LLC injection as determined by real-time PCR. Vehicle, n = 15; celecoxib, n = 15; AMD3100, n = 10; Ep3 KO, n = 5. *P < 0.0001 (ANOVA), P < 0.05 (Student’s t test). Error bars indicate the mean ± SD. N indicates the number of mice tested. S, subcapsular regions; C, cortical regions.