Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion.
Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion.
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DOI：
10.1002/emmm.201302698
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发表时间：
2014-04
影响因子：
11.1
通讯作者：
Grose, Richard P.
中科院分区：
文献类型：
--
作者：
Coleman, Stacey J.;Chioni, Athina-Myrto;Ghallab, Mohammed;Anderson, Rhys K.;Lemoine, Nicholas R.;Kocher, Hemant M.;Grose, Richard P.
胰腺癌的特征是由活化的胰腺星状细胞(PSCs)驱动的促结缔组织增生。FGFs及其受体的过度表达是胰腺癌的一个特征，与预后不良相关，但其表达是否对PSCs的影响尚不清楚。在人类胰腺癌的侵袭前沿，FGF2和FGFR1定位于激活的PSCs的细胞核，但不定位于癌细胞。在体外，使用RNAi或化学抑制法抑制PSCs中的FGFR1和FGF2会显著抑制细胞的增殖，这在癌细胞中是看不到的。在仿生器官型共培养中，抑制FGFR可以阻止PSC和癌细胞的侵袭。抑制FGFR导致FGFR1和FGF2的细胞质定位，而赋形剂治疗条件下，携带核FGFR1和FGF2的PSCs导致癌细胞侵袭潜在的细胞外基质。值得注意的是，在PSCs中，核FGFR1和FGF2的缺失消除了癌细胞的侵袭。这些发现提示了一种新的治疗方法，通过阻止核成纤维细胞生长因子/FGFR介导的PSCs的增殖和侵袭导致肿瘤微环境的破坏，防止胰腺癌细胞的侵袭。
Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.
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