Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis
Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis
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DOI：
10.1074/jbc.m115.669481
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发表时间：
2015-12-11
影响因子：
4.8
通讯作者：
Miyaura, Chisato
中科院分区：
文献类型：
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作者：
Inada, Masaki;Takita, Morichika;Miyaura, Chisato
与肿瘤如黑色素瘤相关的基质细胞是肿瘤生长和转移的重要决定因素。使用膜结合前列腺素E合成酶1（mPges 1（-/-））小鼠，我们表明宿主组织产生的前列腺素E-2（PGE（2））对B16黑色素瘤生长、血管生成和向骨和软组织转移至关重要。同时进行的体外研究表明，成纤维细胞产生的PGE（2）受与B16细胞直接相互作用的调节。PGE（2）的自分泌活性进一步调节成纤维细胞产生血管生成因子，这是原发性和转移性肿瘤生长血管化的关键。类似地，B16细胞和宿主成骨细胞之间的细胞-细胞相互作用调节成骨细胞的mPGES-1活性和PGE（2）产生。PGE（2）反过来又刺激NF-κ B B配体表达的受体活化剂，导致破骨细胞分化和骨侵蚀。使用类二十烷酸受体拮抗剂，我们发现PGE（2）通过EP 4受体作用于肿瘤微环境中的成骨细胞和成纤维细胞。EP 4受体拮抗剂可抑制软组织中的转移性肿瘤生长和血管形成。EP 4-null Ptger 4（-/-）小鼠不支持B16黑色素瘤生长。在体外，EP 4受体拮抗剂调节PGE（2）对成纤维细胞产生血管生成因子的影响。我们的数据表明，B16黑色素瘤细胞直接影响宿主基质细胞产生PGE（2）信号，通过破骨细胞侵蚀活性以及软组织肿瘤中的血管生成来控制骨中的新血管生成和转移性生长。
The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E-2 (PGE(2)) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE(2) production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE(2) further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE(2) production by the osteoblasts. PGE(2), in turn, acts to stimulate receptor activator of NF-kappa B ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE(2) acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE(2) effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE(2) signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors.