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 6

COX-2–derived PGE2-EP3 signaling induces lymphangiogenesis.

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COX-2–derived PGE2-EP3 signaling induces lymphangiogenesis. (A–C) Tempor...
(A–C) Temporal changes in the VEGF-C–positive cell (A), the VEGF-D–positive cell (B), and the VEGFR3-positive cell population (C) in the regional lymph nodes. N indicates the number of mice tested. Vehicle, n = 15; celecoxib, n = 15; Ep3 KO, n = 5. Error bars indicate the mean ± SD. *P < 0.0001 (ANOVA). Student’s t test was used to evaluate significant differences at days 3, 5, and 7 (P < 0.05). (D) Immunofluorescence images of regional lymph nodes stained with the LYVE-1 antibody. Lymphangiogenesis was observed at the efferent side of the regional lymph nodes in vehicle-treated mice from day 3, and was markedly reduced by celecoxib treatment. Scale bars: 100 μm. (E) A schematic presentation of COX-2/SDF-1–dependent premetastatic niche formation. COX-2 and EP3 mediate the increase of SDF-1 at the premetastatic site before the arrival of tumor cells to the regional lymph node. CXCR4-positive tumor cells were mobilized to SDF-1–generating sites. Simultaneously, CXCR4/EP3–positive DCs are recruited to generate SDF-1 in response to EP3 signaling. (F) Tregs are recruited to the premetastatic niche via SDF-1/EP3 signaling. The DCs recruited to the premetastatic niche secrete TGF-β1 in an EP3/SDF-1–dependent manner. Thus, COX-2/PGE2-EP3 signaling together with SDF-1/CXCR4 signaling may decide the fate of the colonizing LLC cells. (G) Fate of metastasized tumor cells. COX-2/EP3 signaling upregulates lymph node lymphangiogenesis in the efferent side of the subcapsular region, and this facilitates tumor cell growth in the regional lymph nodes and lymph node or systemic metastasis.