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PODXL1 promotes metastasis of the pancreatic ductal adenocarcinoma by activating the C5aR/C5a axis from the tumor microenvironment.
Neoplasia ( IF 4.8 ) Pub Date : 2019-11-20 , DOI: 10.1016/j.neo.2019.09.003
Ken Saito 1 , Hidekazu Iioka 1 , Satoshi Maruyama 2 , I Wayan Sumardika 3 , Masakiyo Sakaguchi 3 , Eisaku Kondo 1
Affiliation  

Pancreatic invasive ductal adenocarcinoma (PDAC) is a representative intractable malignancy under the current cancer therapies, and is considered a scirrhous carcinoma because it develops dense stroma. Both PODXL1, a member of CD34 family molecules, and C5aR, a critical cell motility inducer, have gained recent attention, as their expression was reported to correlate with poor prognosis for patients with diverse origins including PDAC; however, previous studies reported independently on their respective biological significance. Here we demonstrate that PODXL1 is essential for metastasis of PDAC cells through its specific interaction with C5aR. In vitro assay demonstrated that PODXL1 bound to C5aR, which stabilized C5aR protein and recruited it to cancer cell plasma membranes to receive C5a, an inflammatory chemoattractant factor. PODXL1 knockout in PDAC cells abrogated their metastatic property in vivo, emulating the liver metastatic mouse model treated with anti-C5a neutralizing antibody. In molecular studies, PODXL1 triggered EMT on PDAC cells in response to stimulation by C5a, corroborating PODXL1 involvement in PDAC cellular invasive properties via specific interaction with the C5aR/C5a axis. Confirming the molecular assays, histological examination showed coexpression of PODXL1 and C5aR at the invasive front of primary cancer nests as well as in liver metastatic foci of PDAC both in the mouse metastasis model and patient tissues. Hence, the novel direct interaction between PODXL1 and the C5aR/C5a axis may provide a better integrated understanding of PDAC biological characteristics including its tumor microenvironment factors.

中文翻译:

PODXL1通过激活肿瘤微环境中的C5aR / C5a轴来促进胰腺导管腺癌的转移。

胰腺浸润性导管腺癌(PDAC)是当前癌症治疗下的一种典型的顽固性恶性肿瘤,由于其发展为致密基质,因此被认为是硬化性癌。CD34家族分子的成员PODXL1和关键的细胞运动诱导剂C5aR都受到了最近的关注,因为据报道它们的表达与包括PDAC在内的多种来源的患者预后差有关。但是,先前的研究独立报告了它们各自的生物学意义。在这里,我们证明PODXL1通过与C5aR的特异性相互作用对于PDAC细胞的转移至关重要。体外测定表明,PODXL1与C5aR结合,该C5aR稳定了C5aR蛋白,并将其募集到癌细胞的质膜上以接受C5a(一种炎症性趋化因子)。PDAC细胞中的PODXL1敲除消除了其体内转移特性,模拟了用抗C5a中和抗体处理的肝转移小鼠模型。在分子研究中,PODXL1响应C5a的刺激而触发PDAC细胞上的EMT,从而证实PODXL1通过与C5aR / C5a轴的特异性相互作用而参与PDAC细胞的侵袭特性。组织学检查证实了分子测定法,在小鼠转移模型和患者组织中,PODXL1和C5aR在原发癌巢侵袭前以及PDAC肝转移灶中共表达。因此,PODXL1和C5aR / C5a轴之间新颖的直接相互作用可能提供对PDAC生物学特性(包括其肿瘤微环境因子)的更好的综合理解。
更新日期:2019-11-01
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