Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients

被引：100

作者：

Jimenez-Valerio, Gabriela ^{[1
]}

Martinez-Lozano, Mar ^{[1
]}

Bassani, Nicklas ^{[1
]}

Vidal, August ^{[2
]}

Ochoa-de-Olza, Maria ^{[3
,4
]}

Suarez, Cristina ^{[4
]}

Garcia-del-Muro, Xavier ^{[3
]}

Carles, Joan ^{[4
]}

Vinals, Francesc ^{[1
,5
]}

Graupera, Mariona ^{[6
]}

Indraccolo, Stefano ^{[7
]}

Casanovas, Oriol ^{[1
]}

机构：

[1] Catalan Inst Oncol IDIBELL, Tumor Angiogenesis Grp, ProCURE, Barcelona 08908, Spain

[2] Bellvitge Univ Hosp, Serv Anatomopathol, Barcelona 08907, Spain

[3] Catalan Inst Oncol, Med Oncol Serv, Barcelona 08908, Spain

[4] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Barcelona 08035, Spain

[5] Univ Barcelona, Dept Ciencies Fisiol 2, Campus Bellvitge, Barcelona 08907, Spain

[6] Bellvitge Biomed Res Inst IDIBELL, Tumor Angiogenesis Grp, Barcelona 08908, Spain

[7] Ist Oncol Veneto IRCCS, I-35128 Padua, Italy

来源：

CELL REPORTS | 2016年 / 15卷 / 06期

基金：

欧洲研究理事会;

关键词：

TARGETED THERAPY; ANGIOGENESIS; HYPOXIA;

D O I：

10.1016/j.celrep.2016.04.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 anti-angiogenics 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.

引用

页码：1134 / 1143

页数：10

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