Mitochondria "fuel" breast cancer metabolism Fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells

被引:142
|
作者
Sotgia, Federica [1 ,4 ,5 ,6 ,7 ]
Whitaker-Menezes, Diana [1 ,6 ,7 ]
Martinez-Outschoorn, Ubaldo E. [1 ,2 ,6 ,7 ]
Salem, Ahmed F. [1 ,6 ,7 ]
Tsirigos, Aristotelis [3 ]
Lamb, Rebecca [4 ,5 ]
Sneddon, Sharon [4 ,5 ]
Hulit, James [4 ,5 ]
Howell, Anthony [4 ,5 ]
Lisanti, Michael P. [1 ,2 ,4 ,5 ,6 ,7 ]
机构
[1] Thomas Jefferson Univ, Kimmel Canc Ctr, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Med Oncol, Philadelphia, PA 19107 USA
[3] IBM Corp, Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA
[4] Univ Manchester, Manchester Acad Hlth Sci Ctr, Inst Canc Sci, Paterson Inst Canc Res,Breakthrough Breast Canc R, Manchester, Lancs, England
[5] Univ Manchester, Manchester Acad Hlth Sci Ctr, Inst Canc Sci, Paterson Inst Canc Res,Manchester Breast Ctr, Manchester, Lancs, England
[6] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA
[7] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA
基金
欧洲研究理事会;
关键词
two-compartment tumor metabolism; mitochondria; oxidative phosphorylation (OXPHOS); mitochondrial biogenesis; mitochondrial translation; cancer metabolism; metabolic reprogramming; LETHAL TUMOR MICROENVIRONMENT; ACUTE MYELOID-LEUKEMIA; CAVEOLIN-1; EXPRESSION; LACTATE PRODUCTION; OXIDATIVE STRESS; GOLGI PHOSPHOPROTEIN-3; AEROBIC GLYCOLYSIS; KETONE PRODUCTION; PROSTATE-CANCER; POOR-PROGNOSIS;
D O I
10.4161/cc.22777
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Here, we present new genetic and morphological evidence that human tumors consist of two distinct metabolic compartments. First, re-analysis of genome-wide transcriptional profiling data revealed that > 95 gene transcripts associated with mitochondrial biogenesis and/or mitochondrial translation were significantly elevated in human breast cancer cells, as compared with adjacent stromal tissue. Remarkably, nearly 40 of these upregulated gene transcripts were mitochondrial ribosomal proteins (MRPs), functionally associated with mitochondrial translation of protein components of the OXPHOS complex. Second, during validation by immunohistochemistry, we observed that antibodies directed against 15 markers of mitochondrial biogenesis and/or mitochondrial translation (AKAP1, GOLPH3, GOLPH3L, MCT1, MRPL40, MRPS7, MRPS15, MRPS22, NRF1, NRF2, PGC1-alpha, POLRMT, TFAM, TIMM9 and TOMM70A) selectively labeled epithelial breast cancer cells. These same mitochondrial markers were largely absent or excluded from adjacent tumor stromal cells. Finally, markers of mitochondrial lipid synthesis (GOLPH3) and mitochondrial translation (POLRMT) were associated with poor clinical outcome in human breast cancer patients. Thus, we conclude that human breast cancers contain two distinct metabolic compartments-a glycolytic tumor stroma, which surrounds oxidative epithelial cancer cells-that are mitochondria-rich. The co-existence of these two compartments is indicative of metabolic symbiosis between epithelial cancer cells and their surrounding stroma. As such, epithelial breast cancer cells should be viewed as predatory metabolic "parasites," which undergo anabolic reprogramming to amplify their mitochondrial "power." This notion is consistent with the observation that the anti-malarial agent chloroquine may be an effective anticancer agent. New anticancer therapies should be developed to target mitochondrial biogenesis and/or mitochondrial translation in human cancer cells.
引用
收藏
页码:4390 / 4401
页数:12
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