PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells.
PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells.
复制标题
DOI：
10.1186/s12885-016-3018-2
复制
发表时间：
2017-01-05
期刊：
影响因子：
3.8
通讯作者：
Lala PK
中科院分区：
文献类型：
--
作者：
Nandi P;Girish GV;Majumder M;Xin X;Tutunea-Fatan E;Lala PK
由淋巴管生成促进的淋巴转移在乳腺癌中很常见，其分子机制仍不完全清楚。我们之前已经表明，人或鼠乳腺癌细胞表达的环氧合酶（COX）-2通过上调肿瘤细胞或肿瘤相关巨噬细胞的VEGF-C/D产生来促进淋巴管生成和淋巴转移，这主要是由于内源性PGE2激活前列腺素受体EP4。目前尚不清楚肿瘤或宿主来源的 PGE2 是否对淋巴管生成有直接影响，如果有，淋巴管内皮细胞 (LEC) 上的 EP4 受体是否发挥任何作用。在这里，我们通过表达 COX-2 和产生 VEGF-C/D 的鼠乳腺癌细胞系 C3L5 和大鼠肠系膜 (RM) LEC 系进行体外研究以及裸鼠体内研究来解决这些问题。 RMLEC 对 PGE2、EP4 激动剂 PGE1OH 或 C3L5 细胞条件培养基 (C3L5-CM) 的反应是在生长因子减少的基质胶上增加增殖、迁移和加速管形成。在选择性 COX-2 抑制剂或 EP4 拮抗剂存在的情况下，RMLEC 在基质胶上形成的天然管被消除。在 COX-2 抑制剂或 EP4 拮抗剂存在的情况下单独添加 PGE2 或 EP4 激动剂或 C3L5-CM 可恢复管形成，增强 EP4 在 RMLEC 在管发生中的作用。这些结果与人真皮 LEC (HMVEC-dLyAd) 和表达 COX-2 的人乳腺癌细胞系 MDA-MB-231 部分重复。在 PGE2、EP4 激动剂或 C3L5-CM 存在或不存在的情况下，在 RMLEC 中用 shRNA 敲低 EP4 会消除它们在基质胶上的成管能力。通过激动剂治疗激活 EP4 后的 RMLEC 肾小管发生依赖于 PI3K/Akt 和 Erk 信号通路以及 VEGFR-3 刺激。最后，在定向体内淋巴管生成测定（DIVLA）中，我们证明了 PGE2 和 EP4 激动剂的体内淋巴管生成以及血管生成能力。这些结果证明了肿瘤以及宿主衍生的 PGE2 在诱导淋巴管生成中的作用，至少部分是通过激活 LEC 上的 EP4 和 VEGFR-3 来实现的。 EP4 是肿瘤和宿主细胞上促进肿瘤相关淋巴管生成的共同靶点，这再次证实了 EP4 拮抗剂在干预乳腺癌淋巴转移中的治疗价值。
Lymphatic metastasis, facilitated by lymphangiogenesis is a common occurrence in breast cancer, the molecular mechanisms remaining incompletely understood. We had earlier shown that cyclooxygenase (COX)-2 expression by human or murine breast cancer cells promoted lymphangiogenesis and lymphatic metastasis by upregulating VEGF-C/D production by tumor cells or tumor-associated macrophages primarily due to activation of the prostaglandin receptor EP4 by endogenous PGE2. It is not clear whether tumor or host-derived PGE2 has any direct effect on lymphangiogenesis, and if so, whether EP4 receptors on lymphatic endothelial cells (LEC) play any role. Here, we address these questions employing in vitro studies with a COX-2-expressing and VEGF-C/D-producing murine breast cancer cell line C3L5 and a rat mesenteric (RM) LEC line and in vivo studies in nude mice. RMLEC responded to PGE2, an EP4 agonist PGE1OH, or C3L5 cell-conditioned media (C3L5-CM) by increased proliferation, migration and accelerated tube formation on growth factor reduced Matrigel. Native tube formation by RMLEC on Matrigel was abrogated in the presence of a selective COX-2 inhibitor or an EP4 antagonist. Addition of PGE2 or EP4 agonist, or C3L5-CM individually in the presence of COX-2 inhibitor, or EP4 antagonist, restored tube formation, reinforcing the role of EP4 on RMLEC in tubulogenesis. These results were partially duplicated with a human dermal LEC (HMVEC-dLyAd) and a COX-2 expressing human breast cancer cell line MDA-MB-231. Knocking down EP4 with shRNA in RMLEC abrogated their tube forming capacity on Matrigel in the absence or presence of PGE2, EP4 agonist, or C3L5-CM. RMLEC tubulogenesis following EP4 activation by agonist treatment was dependent on PI3K/Akt and Erk signaling pathways and VEGFR-3 stimulation. Finally in a directed in vivo lymphangiogenesis assay (DIVLA) we demonstrated the lymphangiogenic as well as angiogenic capacity of PGE2 and EP4 agonist in vivo. These results demonstrate the roles of tumor as well as host-derived PGE2 in inducing lymphangiogenesis, at least in part, by activating EP4 and VEGFR-3 on LEC. EP4 being a common target on both tumor and host cells contributing to tumor-associated lymphangiogenesis reaffirms the therapeutic value of EP4 antagonists in the intervention of lymphatic metastasis in breast cancer.
登录
查看更多内容
影响因子：
3.8
作者：
Fujii T;Tabe Y;Yajima R;Yamaguchi S;Tsutsumi S;Asao T;Kuwano H
通讯作者：
Kuwano H
DOI：
10.1097/igc.0b013e31820575db
发表时间：
2011-02-01
影响因子：
4.8
作者：
Haller, Herman;Mamula, Ozren;Perovic, Danko
通讯作者：
Perovic, Danko
影响因子：
6.4
作者：
LALA, PK;PARHAR, RS
通讯作者：
PARHAR, RS
影响因子：
4.8
作者：
Pan, Mei-Ren;Hou, Ming-Feng;Hung, Wen-Chun
通讯作者：
Hung, Wen-Chun
影响因子：
5.2
作者：
Majumder, Mousumi;Xin, Xiping;Lala, Peeyush K.
通讯作者：
Lala, Peeyush K.