The reverse Warburg effect Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts

被引：233

作者：

Bonuccelli, Gloria ^{[1
,2
,3
]}

Whitaker-Menezes, Diana ^{[1
,2
,3
]}

Castello-Cros, Remedios ^{[1
,2
,3
]}

Pavlides, Stephanos ^{[1
,2
,3
]}

Pestell, Richard G. ^{[1
,2
,3
]}

Fatatis, Alessandro ^{[7
,8
]}

Witkiewicz, Agnieszka K. ^{[4
,5
]}

Vander Heiden, Matthew G. ^{[9
]}

Migneco, Gemma ^{[1
,2
,3
]}

Chiavarina, Barbara ^{[1
,2
,3
]}

Frank, Philippe G. ^{[1
,2
,3
]}

Capozza, Franco ^{[1
,2
,3
]}

Flomenberg, Neal ^{[6
]}

Martinez-Outschoorn, Ubaldo E. ^{[1
,2
,3
,6
]}

Sotgia, Federica ^{[1
,2
,3
]}

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

机构：

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

[2] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA

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

[4] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA

[5] Thomas Jefferson Univ, Dept Anat & Cell Biol, Philadelphia, PA 19107 USA

[6] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[7] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, Philadelphia, PA 19104 USA

[8] Drexel Univ, Coll Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[9] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

来源：

CELL CYCLE | 2010年 / 9卷 / 10期

关键词：

caveolin-1; tumor stroma; myofibroblast; cancer associated fibroblast; aerobic glycolysis; M2-isoform of pyruvate kinase; lactate dehydrogenase; Warburg effect; BREAST-CANCER; MITOCHONDRIAL STAT3; STROMAL CAVEOLIN-1; EXPRESSION; TUMORIGENESIS; CELLS; INVASIVENESS; HYPERPLASIA; PROGRESSION; THERAPY;

D O I：

10.4161/cc.9.10.11601

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：

We and others have previously identified a loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts (CAFs) as a powerful single independent predictor of breast cancer patient tumor recurrence, metastasis, tamoxifen-resistance and poor clinical outcome. However, it remains unknown how loss of stromal Cav-1 mediates these effects clinically. To mechanistically address this issue, we have now generated a novel human tumor xenograft model. In this two-component system, nude mice are co-injected with (i) human breast cancer cells (MDA-MB-231), and (ii) stromal fibroblasts (wild-type (WT) versus Cav-1 (-/-) deficient). This allowed us to directly evaluate the effects of a Cav-1 deficiency solely in the tumor stromal compartment. Here, we show that Cav-1-deficient stromal fibroblasts are sufficient to promote both tumor growth and angiogenesis, and to recruit Cav-1 (+) micro-vascular cells. Proteomic analysis of Cav-1-deficient stromal fibroblasts indicates that these cells upregulate the expression of glycolytic enzymes, a hallmark of aerobic glycolysis (the Warburg effect). Thus, Cav-1-deficient stromal fibroblasts may contribute towards tumor growth and angiogenesis, by providing energy-rich metabolites in a paracrine fashion. We have previously termed this new idea the "Reverse Warburg Effect". In direct support of this notion, treatment of this xenograft model with glycolysis inhibitors functionally blocks the positive effects of Cav-1-deficient stromal fibroblasts on breast cancer tumor growth. Thus, pharmacologically-induced metabolic restriction (via treatment with glycolysis inhibitors) may be a promising new therapeutic strategy for breast cancer patients that lack stromal Cav-1 expression. We also identify the stromal expression of PKM2 and LDH-B as new candidate biomarkers for the "Reverse Warburg Effect" or "Stromal-Epithelial Metabolic Coupling" in human breast cancers.

引用

页码：1960 / 1971

页数：12

共 26 条

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