Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells

被引：350

作者：

Wang, Yuan Yuan ^{[1
,2
,3
]}

Attane, Camille ^{[2
,9
,10
,11
,12
]}

Milhas, Delphine ^{[1
]}

Dirat, Beatrice ^{[1
,2
]}

Dauvillier, Stephanie ^{[1
]}

Guerard, Adrien ^{[1
]}

Gilhodes, Julia ^{[4
]}

Lazar, Ikrame ^{[1
,13
]}

Alet, Nathalie ^{[5
]}

Laurent, Victor ^{[1
,14
]}

Le Gonidec, Sophie ^{[2
]}

Biard, Denis ^{[6
]}

Herve, Caroline ^{[5
]}

Bost, Frederic ^{[7
]}

Ren, Guo Sheng ^{[3
]}

Bono, Francoise ^{[5
]}

Escourrou, Ghislaine ^{[8
]}

Prentki, Marc ^{[9
,10
,11
,12
]}

Nieto, Laurence ^{[1
]}

Valet, Philippe ^{[2
]}

Muller, Catherine ^{[1
]}

机构：

[1] Univ Toulouse, IPBS, Toulouse, France

[2] Univ Toulouse, INSERM, UPS, Inst Malad Metab & Cardiovasc I2MC, Toulouse, France

[3] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing, Peoples R China

[4] Inst Univ Canc, Dept Biostat, Toulouse, France

[5] EVOTEC France, Toulouse, France

[6] CEA, DSV, IMETI SEPIA, Paris, France

[7] INSERM, U1065, Ctr Mediterraneen Med Mol, Nice, France

[8] Inst Univ Canc, Serv Anatomopathol, Toulouse, France

[9] CRCHUM, Dept Nutr, Montreal, PQ, Canada

[10] CRCHUM, Dept Biochem, Montreal, PQ, Canada

[11] CRCHUM, Montreal Diabet Res Ctr, Montreal, PQ, Canada

[12] Univ Montreal, Montreal, PQ, Canada

[13] Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, BAT GALIM, Haifa, Israel

[14] IDC Helmholtz Ctr Munich, Inst Diabet & Canc, Munich, Germany

来源：

JCI INSIGHT | 2017年 / 2卷 / 04期

关键词：

FATTY-ACID OXIDATION; MITOCHONDRIAL STRUCTURE; ENERGY-METABOLISM; BETA-OXIDATION; PROGRESSION; DIFFERENTIATION; 2-DEOXYGLUCOSE; INHIBITION; EXPRESSION; CONTRIBUTE;

D O I：

10.1172/jci.insight.87489

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase-dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid beta-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression.

引用

页数：20

共 53 条

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