Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.
Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.
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DOI：
10.1136/gutjnl-2020-322493
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发表时间：
2022-01
期刊：
影响因子：
24.5
通讯作者：
Duda DG
中科院分区：
文献类型：
--
作者：
Aoki S;Inoue K;Klein S;Halvorsen S;Chen J;Matsui A;Nikmaneshi MR;Kitahara S;Hato T;Chen X;Kawakubo K;Nia HT;Chen I;Schanne DH;Mamessier E;Shigeta K;Kikuchi H;Ramjiawan RR;Schmidt TC;Iwasaki M;Yau T;Hong TS;Quaas A;Plum PS;Dima S;Popescu I;Bardeesy N;Munn LL;Borad MJ;Sassi S;Jain RK;Zhu AX;Duda DG
肝内胆管癌（ICC）是一种罕见的肝脏恶性肿瘤，治疗方案有限，其特征是侵袭性进展、结缔组织增生和血管异常。本研究的目的是确定胎盘生长因子（PlGF）在ICC进展中的作用。我们评估了ICC患者标本中PlGF的表达，并评估了PlGF在原位移植ICC小鼠模型中遗传或药物抑制的治疗效果。我们使用体外3d共培养系统评估了PlGF刺激或阻断对ICC细胞和癌症相关成纤维细胞（CAFs）的影响。PlGF水平在人ICC基质细胞和循环血浆中升高，并与疾病进展相关。单细胞RNA测序显示，PlGF阻断对小鼠的主要影响是静止caf的富集，其特征是与Akt通路、糖酵解和缺氧信号通路相关的高基因转录水平。PlGF阻断抑制icc源性CAFs中Akt磷酸化和肌成纤维细胞活化。PlGF阻断还减少了结缔组织增生和组织僵硬，导致塌陷的肿瘤血管重新开放，改善了血液灌注，同时减少了ICC细胞的侵袭。此外，PlGF阻断可增强小鼠携带ICC的标准化疗的疗效。结论PlGF阻断可减少侵袭性ICC小鼠的肿瘤内缺氧和转移性传播，增强化疗敏感性，提高生存率。
Intrahepatic cholangiocarcinoma (ICC)—a rare liver malignancy with limited therapeutic options—is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
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影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
13.5
作者：
Fingas, Christian D.;Bronk, Steven F.;Werneburg, Nathan W.;Mott, Justin L.;Guicciardi, Maria E.;Cazanave, Sophie C.;Mertens, Joachim C.;Sirica, Alphonse E.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
64.5
作者：
Fischer, Christian;Jonckx, Bart;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
82.9
作者：
Carmeliet, P;Moons, L;Persico, MG
通讯作者：
Persico, MG
影响因子：
50.3
作者：
Costa, Ana;Kieffer, Yann;Mechta-Grigoriou, Fatima
通讯作者：
Mechta-Grigoriou, Fatima