Ketones and lactate "fuel" tumor growth and metastasis Evidence that epithelial cancer cells use oxidative mitochondrial metabolism

被引：523

作者：

Bonuccelli, Gloria ^{[1
,3
]}

Tsirigos, Aristotelis ^{[4
]}

Whitaker-Menezes, Diana ^{[1
,3
]}

Pavlides, Stephanos ^{[1
,3
]}

Pestell, Richard G. ^{[1
,3
]}

Chiavarina, Barbara ^{[1
,3
]}

Frank, Philippe G. ^{[1
,3
]}

Flomenberg, Neal ^{[2
]}

Howell, Anthony ^{[5
,6
]}

Martinez-Outschoorn, Ubaldo E. ^{[1
,2
,3
]}

Sotgia, Federica ^{[1
,3
,5
,6
]}

Lisanti, Michael P. ^{[1
,2
,3
,5
,6
]}

机构：

[1] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA

[3] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[4] IBM Thomas J Watson Res Ctr, Computat Genom Grp, Yorktown Hts, NY USA

[5] Univ Manchester, Manchester Breast Ctr, Manchester M13 9PL, Lancs, England

[6] Univ Manchester, Breakthrough Breast Canc Res Unit, Sch Canc Enabling Sci & Technol, Paterson Inst Canc Res,Manchester Acad Hlth Sci C, Manchester M13 9PL, Lancs, England

来源：

CELL CYCLE | 2010年 / 9卷 / 17期

基金：

欧洲研究理事会;

关键词：

3-hydroxybutyrate (ketone bodies); L-lactate; stroma; tumor growth; metastasis; the Warburg effect; aerobic glycolysis; tumor microenvironment; cancer associated fibroblasts; LACTIC-ACIDOSIS; BREAST-CANCER; STROMAL CAVEOLIN-1; UNDIFFERENTIATED CARCINOMA; PROGNOSTIC-FACTORS; EXPRESSION; FIBROBLASTS; GLYCOLYSIS; SURVIVAL; DISEASE;

D O I：

10.4161/cc.9.17.12731

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Previously, we proposed a new model for understanding the "Warburg effect" in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm "The Reverse Warburg Effect." Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by similar to 2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by similar to 10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the "Reverse Warburg Effect." Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer's or Hartmann's solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.

引用

页码：3506 / 3514

页数：9

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