Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors.
Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors.
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DOI：
10.18632/oncotarget.16942
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发表时间：
2017-06-13
期刊：
影响因子：
--
通讯作者：
Michieli P
中科院分区：
文献类型：
--
作者：
Mira A;Morello V;Céspedes MV;Perera T;Comoglio PM;Mangues R;Michieli P
在异种移植模型中，由于小鼠肝细胞生长因子(HGF)不能完全激活人MET，因此旁分泌肝细胞生长因子(HGF)在抗血管生成抑制剂(AIS)中的作用被隐藏。为了揭示它，我们比较了AIS在野生型和人HGF敲入SCID小鼠身上的疗效，这些小鼠携带着原位的人结肠肿瘤。物种特异性的HGF/MET信号显著削弱了对抗血管生成药物的反应，并促进了转移扩散。在模拟抗血管生成治疗后果的基于细胞的分析中，结直肠癌细胞对缺氧完全耐受，但对营养剥夺极其敏感。HGF可阻止饥饿诱导的细胞凋亡，促进GLUT1介导的葡萄糖摄取、持续糖酵解和激活的自噬。GLUT1在葡萄糖存在下的药理抑制作用与无糖作用一样有效地杀死肿瘤细胞，这种作用可被HGF拮抗。同时靶向GLUT1和HGF有效地抑制了抗AI的人类肿瘤在人HGF敲入SCID小鼠中的生长和扩散，而不会加剧肿瘤的缺氧。这些数据表明，基质来源的HGF保护结直肠癌细胞免受葡萄糖饥饿诱导的凋亡，促进对AIS和抗糖酵解药物的抵抗。联合抑制葡萄糖代谢和HGF/MET信号转导(“抗代谢疗法”)可能比完全阻断肿瘤血供更有效地治疗结直肠癌。
The role of paracrine Hepatocyte Growth Factor (HGF) in the resistance to angiogenesis inhibitors (AIs) is hidden in xenograft models because mouse HGF fails to fully activate human MET. To uncover it, we compared the efficacy of AIs in wild-type and human HGF knock-in SCID mice bearing orthotopic human colorectal tumors. Species-specific HGF/MET signaling dramatically impaired the response to anti-angiogenic agents and boosted metastatic dissemination. In cell-based assays mimicking the consequences of anti-angiogenic therapy, colorectal cancer cells were completely resistant to hypoxia but extremely sensitive to nutrient deprivation. Starvation-induced apoptosis could be prevented by HGF, which promoted GLUT1-mediated glucose uptake, sustained glycolysis and activated autophagy. Pharmacological inhibition of GLUT1 in the presence of glucose killed tumor cells as effectively as glucose deprivation, and this effect was antagonized by HGF. Concomitant targeting of GLUT1 and HGF potently suppressed growth and dissemination of AI-resistant human tumors in human HGF knock-in SCID mice without exacerbating tumor hypoxia. These data suggest that stroma-derived HGF protects CRC cells against glucose starvation-induced apoptosis, promoting resistance to both AIs and anti-glycolytic agents. Combined inhibition of glucose metabolism and HGF/MET signaling (‘anti-METabolic therapy’) may represent a more effective CRC treatment compared to utterly blocking tumor blood supply.
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用FDA批准的利托那韦和二甲双胍靶向多发性骨髓瘤的代谢可塑性。
DOI：
10.1158/1078-0432.ccr-14-1088
发表时间：
2015-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dalva-Aydemir S;Bajpai R;Martinez M;Adekola KU;Kandela I;Wei C;Singhal S;Koblinski JE;Raje NS;Rosen ST;Shanmugam M
通讯作者：
Shanmugam M
影响因子：
4.8
作者：
Bertola, Adeline;Bonnafous, Stephanie;Gual, Philippe
通讯作者：
Gual, Philippe
DOI：
10.2147/dddt.s31442
发表时间：
2013
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Cowey CL
通讯作者：
Cowey CL
DOI：
10.1158/1078-0432.ccr-12-2123
发表时间：
2013-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brauer HA;Makowski L;Hoadley KA;Casbas-Hernandez P;Lang LJ;Romàn-Pèrez E;D'Arcy M;Freemerman AJ;Perou CM;Troester MA
通讯作者：
Troester MA
影响因子：
8.8
作者：
Jiménez-Valerio G;Martínez-Lozano M;Bassani N;Vidal A;Ochoa-de-Olza M;Suárez C;García-Del-Muro X;Carles J;Viñals F;Graupera M;Indraccolo S;Casanovas O
通讯作者：
Casanovas O