A soluble form of Siglec-9 provides an antitumor benefit against mammary tumor cells expressing MUC1 in transgenic mice.
A soluble form of Siglec-9 provides an antitumor benefit against mammary tumor cells expressing MUC1 in transgenic mice.
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DOI：
10.1016/j.bbrc.2014.06.009
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发表时间：
2014-07
影响因子：
3.1
通讯作者：
Y. Tomioka;M. Morimatsu;K. Nishijima;T. Usui;Sayo Yamamoto;Haruka Suyama;K. Ozaki;Toshihiro Ito;E. Ono
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文献类型：
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作者：
Y. Tomioka;M. Morimatsu;K. Nishijima;T. Usui;Sayo Yamamoto;Haruka Suyama;K. Ozaki;Toshihiro Ito;E. Ono
肿瘤相关MUC 1与Siglec-9结合，预期其介导肿瘤细胞生长和负性免疫调节。我们假设可溶形式的Siglec-9（sSiglec-9）竞争性地抑制MUC 1与其受体分子（如人Siglec-9）的结合，导致提供针对MUC 1表达肿瘤的抗肿瘤益处，并产生表达sSiglec-9（sSiglec-9 Tg）的转基因小鼠系。当将表达MUC 1的乳腺肿瘤细胞腹膜内移植到sSiglec-9 Tg中时，与非转基因小鼠相比，肿瘤增殖较慢，组织学恶性程度较低。在sSiglec-9 Tg的肿瘤引起的腹水中检测到sSiglec-9，并且sSiglec-9和MUC 1通常共定位在肿瘤细胞的表面上。PCNA免疫组织化学还揭示了sSiglec-9 Tg中肿瘤细胞的增殖减少。在具有显著抑制肿瘤增殖的sSiglec-9 Tg中，MUC 1表达有降低的趋势。在携带肿瘤的sSiglec-9 Tg的腹水中，T细胞均匀浸润，而在非转基因小鼠中经常观察到变性T细胞的聚集。这些结果表明，sSiglec-9对转基因小鼠中表达MUC 1的肿瘤具有抗肿瘤益处，这可以避免负性免疫调节和/或抑制肿瘤相关的MUC 1下游信号转导以及随后的肿瘤增殖。
Tumor-associated MUC1 binds to Siglec-9, which is expected to mediate tumor cell growth and negative immunomodulation. We hypothesized that a soluble form of Siglec-9 (sSiglec-9) competitively inhibits a binding of MUC1 to its receptor molecules like human Siglec-9, leading to provide antitumor benefit against MUC1-expressing tumor, and generated transgenic mouse lines expressing sSiglec-9 (sSiglec-9 Tg). When mammary tumor cells expressing MUC1 were intraperitoneally transplanted into sSiglec-9 Tg, tumor proliferation was slower with the lower histological malignancy as compared with non-transgenic mice. The sSiglec-9 was detected in the ascites caused by the tumor in the sSiglec-9 Tg, and sSiglec-9 and MUC1 were often colocalized on surfaces of the tumor cells. PCNA immunohistochemistry also revealed the reduced proliferation of the tumor cells in sSiglec-9 Tg. In sSiglec-9 Tg with remarkable suppression of tumor proliferation, MUC1 expressions were tend to be reduced. In the ascites of sSiglec-9 Tg bearing the tumor, T cells were uniformly infiltrated, whereas aggregations of degenerative T cells were often observed in the non-transgenic mice. These results suggest that sSiglec-9 has an antitumor benefit against MUC1-expressing tumor in the transgenic mice, which may avoid the negative immunomodulation and/or suppress tumor-associated MUC1 downstream signal transduction, and subsequent tumor proliferation.