Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy.
Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy.
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DOI：
10.1016/j.ccell.2016.10.006
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发表时间：
2016-12-12
期刊：
影响因子：
50.3
通讯作者：
Carmeliet P
中科院分区：
文献类型：
--
作者：
Cantelmo AR;Conradi LC;Brajic A;Goveia J;Kalucka J;Pircher A;Chaturvedi P;Hol J;Thienpont B;Teuwen LA;Schoors S;Boeckx B;Vriens J;Kuchnio A;Veys K;Cruys B;Finotto L;Treps L;Stav-Noraas TE;Bifari F;Stapor P;Decimo I;Kampen K;De Bock K;Haraldsen G;Schoonjans L;Rabelink T;Eelen G;Ghesquière B;Rehman J;Lambrechts D;Malik AB;Dewerchin M;Carmeliet P
异常的肿瘤血管促进转移，影响化疗。因此，肿瘤血管正常化(TVN)作为抗癌治疗应运而生。在这里，我们展示了肿瘤内皮细胞(ECs)具有高糖酵解代谢，将中间产物分流到核苷酸合成。EC半缺失或阻断糖酵解激活剂PFKFB3并不影响肿瘤的生长，但通过使肿瘤血管正常化来减少癌细胞的侵袭、血管内和转移，从而促进血管成熟和灌流。在机制上，PFKFB3抑制通过减少内皮细胞的VE-钙粘蛋白内吞作用来加强血管屏障，并通过糖酵解减少使周细胞更静止和更粘连(通过上调N-钙粘附素)；它还通过减少NF-κB信号来降低内皮细胞中癌细胞黏附分子的表达。PFKFB3阻断治疗也改善了原发和转移性肿瘤的化疗。
Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyper-glycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-κB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors.
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