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 1

COX-2 induction in regional lymph nodes and the effect of COX-2 inhibition on regional LNM.

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COX-2 induction in regional lymph nodes and the effect of COX-2 inhibiti...
(A) Immunohistochemical COX-2 staining of the regional lymph nodes after lung LLC cell implantation. In vehicle-treated mice, COX-2–positive cells were localized in the subcapsular regions. Celecoxib was given orally throughout the experimental period. Scale bar: 50 μm. (B) RT-PCR analysis of Cox2. Cox2 mRNA levels were significantly reduced in the celecoxib-treated group compared with the vehicle-treated group. n = 15 per group. *P < 0.0001 (ANOVA). (C) The percentage total cell population of COX-2–positive cells was significantly reduced in the celecoxib-treated group compared with the vehicle-treated group. n = 15 per group. *P < 0.0001 (ANOVA). (D) Loupe images by typical H&E staining obtained on day 10 after injection. Scale bars: 5 mm. (E) Fluorescence microscope images obtained after implantation of GFP-positive LLC cells into the lung. Scale bars: 3 mm. (F) Temporal changes in the percentage of regional LNM–positive mice. Metastasis in the vehicle-treated group was compared with that in the celecoxib-treated group. n = 15 per group. *P < 0.0001 (χ2 test). (G) Percentage of regional LNM–positive mice. Metastasis was compared between Ep3 KO mice and WT mice. WT, n = 15; Ep3 KO, n = 5. *P < 0.05 (χ2 test). Error bars indicate the mean ± SD. N indicates the number of mice tested. S, subcapsular regions; C, cortex; PT, primary tumor; LN, lymph node; T, thymus.