S100P antibody-mediated therapy as a new promising strategy for the treatment of pancreatic cancer.
S100P antibody-mediated therapy as a new promising strategy for the treatment of pancreatic cancer.
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DOI：
10.1038/oncsis.2014.7
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发表时间：
2014-03-17
期刊：
影响因子：
6.2
通讯作者：
Hernandez, J. L.
中科院分区：
文献类型：
--
作者：
Dakhel, S.;Padilla, L.;Adan, J.;Masa, M.;Martinez, J. M.;Roque, L.;Coll, T.;Hervas, R.;Calvis, C.;Messeguer, R.;Mitjans, F.;Hernandez, J. L.
尽管在诊断和治疗方面取得了进展，但胰腺癌仍然是所有实体恶性肿瘤中预后最差的。近年来的研究表明，促转移蛋白S100 P通过细胞外功能促进胰腺癌的增殖、生存、侵袭和转移。此外，它的表达与几种类型癌症患者的不良预后密切相关，尽管负责不同生物学功能的整个分子机制尚未完全了解。我们发现细胞外S100 P通过促进细胞增殖刺激胰腺癌BxPC 3细胞系。S100 P可诱导IκBα磷酸化和基质金属蛋白酶9（MMP-9）分泌。此外，用S100 P处理保护细胞免受细胞毒性剂吉西他滨诱导的损伤。在这些结果的基础上，我们开发了功能阻断性抗S100 P单克隆抗体（mAb），消除了其所有的体外活性。此外，在皮下和原位BxPC 3肿瘤模型中，用候选2 H8抗体进行的体内治疗降低了肿瘤生长和肝转移形成。我们得出结论，通过特异性mAb阻断S100 P细胞外活性的治疗策略可能是一种有吸引力的治疗方法，作为单一药物或与靶向或化疗药物联合治疗胰腺癌。
Despite progresses in diagnosis and treatment, pancreatic cancer continues to have the worst prognosis of all solid malignant tumors. Recent evidences suggest that the metastasis-promoting protein S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression through extracellular functions. Moreover, its expression is strongly correlated with poor prognosis in patients with several types of cancer although the entire molecular mechanism responsible for the diverse biological functions is not fully understood. We showed that extracellular S100P stimulates pancreatic carcinoma BxPC3 cell line by promoting cell proliferation. We also demonstrated that S100P induces, in this cell line, the phosphorylation of IκBα and the secretion of matrix metalloproteinase 9 (MMP-9). In addition, treatment with S100P protected cells from injuries induced by the cytotoxic agent Gemcitabine. On the basis of these results, we developed function-blocking anti-S100P monoclonal antibodies (mAbs) that abolished all of its in vitro activities. Furthermore, in vivo treatment with the candidate 2H8 antibody decreased tumor growth and liver metastasis formation in a subcutaneous and orthotopic BxPC3 tumor model. We conclude here that a therapeutic strategy blocking the extracellular activity of S100P by means of specific mAbs could be an attractive therapeutic approach as a single agent or in combination with target-directed or chemotherapeutic drugs to treat pancreatic cancer.
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DOI：
10.12659/msm.889636
发表时间：
2013-10-31
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Fang Y;Yao Q;Chen Z;Xiang J;William FE;Gibbs RA;Chen C
通讯作者：
Chen C
影响因子：
3.9
作者：
Fuentes, Maren K.;Nigavekar, Shraddha S.;Huang, Emina H.
通讯作者：
Huang, Emina H.
影响因子：
10.8
作者：
Bond, M;Chase, AJ;Newby, AC
通讯作者：
Newby, AC
影响因子：
11.2
作者：
Bulk, Etmar;Hascher, Anoe;Mueller-Tidow, Carsten
通讯作者：
Mueller-Tidow, Carsten
影响因子：
1.8
作者：
Koy, Mirja;Hambruch, Nina;Schuberth, Hans-Joachim
通讯作者：
Schuberth, Hans-Joachim