Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction.
Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction.
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DOI：
10.7150/jca.24415
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发表时间：
2018
影响因子：
3.9
通讯作者：
Kondo E
中科院分区：
文献类型：
--
作者：
Saito K;Sakaguchi M;Maruyama S;Iioka H;Putranto EW;Sumardika IW;Tomonobu N;Kawasaki T;Homma K;Kondo E
胰腺导管腺癌（PDAC）是目前最难治疗的恶性肿瘤之一，其组织学表现为典型的硬结型。由于其丰富的肿瘤间质和缺乏血管化，化疗药物被认为是无效渗透癌巢，使其非常难以治愈的患者与PDAC。然而，PDAC也被认为是由于其棘手的其他关键因素，如肿瘤细胞和肿瘤微环境之间的细胞相互作用以及结构屏障，这增加了治疗抗性。在这里，我们报告了PDAC细胞和间充质干细胞（MSC）之间的特定细胞相互作用，混合在PDAC基质中，这有利于癌症的侵袭。分泌表型分析显示，双调蛋白（AREG）和MMP-3的产生在BxPC 3细胞与人MSC共存下特异性上调（与单独的BxPC 3细胞相比，AREG中约4至10倍，MMP-3中约20至60倍），而MMP-9的表达降低（与单独的BxPC 3细胞相比，不到十分之一）。通过其特异性siRNA阻断AREG的产生消除了MSC介导的BxPC 3侵袭力的驱动力。免疫组化分析PDAC患者和PDAC模拟小鼠异种移植模型的组织样本显示，在浸润前沿的癌细胞上检测到AREG及其受体EGFR的显著共表达。这些结果有力地表明，PDAC基质中癌细胞和MSC之间的细胞相互作用可能对癌症进展至关重要，特别是在局部侵袭和转移的早期发展过程中。
Pancreatic ductal adenocarcinoma (PDAC) is currently one of the most intractable malignancies with a typical scirrhous pattern in histology. Due to its abundant tumor stroma and scant vascularization, chemotherapeutic agents are considered inefficiently permeable to cancer nests, making it highly difficult to cure the patients with PDAC. However, PDAC is also considered to owe its intractability to other critical factors such as cellular interaction between tumor cells and tumor microenvironment as well as architectural barriers, which increases in therapeutic resistance. Here, we report a specific cellular interaction between PDAC cells and mesenchymal stem cells (MSCs) intermingled in PDAC stroma, which facilitates cancer invasion. Secretory phenotype profiling revealed that production of Amphiregulin (AREG) and MMP-3 were specifically upregulated under the coexistence of BxPC3 cells with human MSCs (approximately four to ten folds in AREG, and twenty to sixty-folds in MMP-3 compared to that of BxPC3 cells alone), whereas MMP-9 expression was decreased (less than one-tenth comparing with that of BxPC3 cells alone). Blockage of AREG production by its specific siRNA removed MSC-mediated driving force of BxPC3 invasiveness. Immunohistochemical analysis of tissue samples obtained both from PDAC patients and PDAC imitating mouse xenografted models revealed that significant coexpression of AREG and its receptor EGFR were detected on the cancer cells at invasive front. These results strongly suggested that cellular interaction between cancer cells and MSCs in the PDAC stroma might be critical to cancer progression, especially in the process of local invasion and the early stage development of metastasis.
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影响因子：
2.7
作者：
Wang, Lin;Zhu, Zhi-Xia;Zhang, Wei-Min
通讯作者：
Zhang, Wei-Min
影响因子：
5
作者：
Bolm L;Cigolla S;Wittel UA;Hopt UT;Keck T;Rades D;Bronsert P;Wellner UF
通讯作者：
Wellner UF
影响因子：
4.3
作者：
Xu, Zhihong;Pothula, Srinivasa P.;Apte, Minoti V.
通讯作者：
Apte, Minoti V.
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
28.5
作者：
von Ahrens D;Bhagat TD;Nagrath D;Maitra A;Verma A
通讯作者：
Verma A