Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients.
Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients.
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DOI：
10.1016/j.celrep.2016.04.015
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发表时间：
2016-05-10
期刊：
影响因子：
8.8
通讯作者：
Casanovas O
中科院分区：
文献类型：
--
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
抗血管生成药物在临床上被用作治疗肾细胞癌（RCC）的标准一线治疗。然而，这些药物主要用于稳定疾病，并且耐药性最终伴随着疾病进展而发展。在这里，我们牵连的代谢共生之间的肿瘤细胞远端和近端剩余的血管作为抗血管生成治疗的耐药机制，在患者来源的RCC orthoxenograft（PDX）模型和临床样本。这种代谢模式受mTOR途径调节，其抑制有效阻断PDX模型中的代谢共生。临床上，抗血管生成药物治疗的患者始终存在代谢共生的组织学特征，这些特征在耐药肿瘤中加重。此外，mTOR途径也与临床样品相关，其抑制消除了患者样品中的共生模式。总体而言，这些数据支持抗血管生成药物的耐药机制，涉及肿瘤细胞的代谢区室化，可被mTOR靶向药物抑制。对抗血管生成治疗的抗性涉及RCC中的代谢共生模式mTOR途径介导这种抗性，并且mTOR抑制阻断代谢共生。在患者中，抗血管生成药物主要在抗性肿瘤中诱导共生模式，在用抗血管生成药物治疗的患者中也提示了mTOR途径的含义。描述了RCC中对抗血管生成药物的抗性机制，其涉及肿瘤细胞之间的代谢共生模式，其可以用mTOR抑制剂阻断。在患者中的验证表明，抗血管生成药物产生相同的代谢共生模式，主要是在耐药肿瘤中，涉及mTOR通路。
Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs. Resistance to antiangiogenic therapy involves metabolic symbiosis patterning in RCC mTOR pathway mediates this resistance and mTOR inhibition blocks metabolic symbiosis In patients, antiangiogenics induce symbiotic patterning mostly in resistant tumors mTOR pathway implication is also suggested in patients treated with antiangiogenics Jimenez-Valerio et al. describe a mechanism of resistance to antiangiogenics in RCC that involves metabolic symbiosis patterning between tumor cells that can be blocked with mTOR inhibitors. Validation in patients demonstrates that antiangiogenics produce the same metabolic symbiosis pattern, mostly in resistant tumors, with mTOR pathway involvement.