Mitochondrial metabolism in cancer metastasis

Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue

Federica Sotgia, Diana Whitaker-Menezes, Ubaldo E. Martinez-Outschoorn, Neal Flomenberg, Ruth C. Birbe, Agnieszka K. Witkiewicz, Anthony Howell, Nancy J. Philp, Richard G. Pestell, Michael P. Lisanti

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the "reverse Warburg effect," because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the "reverse Warburg effect,"our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TO MM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally "fuels" tumor progression and metastatic dissemination, by "feeding" mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TO MM20(-) "glycolytic" cancer cells were rarely observed, indicating that the conventional "Warburg effect" does not frequently occur in cancer-positive lymph node metastases.

Original languageEnglish (US)
Pages (from-to)1445-1454
Number of pages10
JournalCell Cycle
Volume11
Issue number7
DOIs
StatePublished - Apr 1 2012

Fingerprint

Mitochondria
Lymph Nodes
Neoplasm Metastasis
Neoplasms
Stromal Cells
Breast Neoplasms
Ketone Bodies
Energy Transfer
Glycolysis
Adipocytes
Energy Metabolism
Lactic Acid
Epithelial Cells
Staining and Labeling
Inflammation
Growth

Keywords

  • Caveolin-1
  • Complex IV
  • Inflammation
  • MCT4
  • Metabolic coupling
  • Metastasis
  • Mitochondria
  • Monocarboxylic acid transporter
  • Oxidative stress
  • OXPHOS
  • SLC16A3
  • TOMM20
  • Tumor stroma
  • Two-compartment tumor metabolism

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Sotgia, F., Whitaker-Menezes, D., Martinez-Outschoorn, U. E., Flomenberg, N., Birbe, R. C., Witkiewicz, A. K., ... Lisanti, M. P. (2012). Mitochondrial metabolism in cancer metastasis: Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue. Cell Cycle, 11(7), 1445-1454. https://doi.org/10.4161/cc.19841

Mitochondrial metabolism in cancer metastasis : Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue. / Sotgia, Federica; Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E.; Flomenberg, Neal; Birbe, Ruth C.; Witkiewicz, Agnieszka K.; Howell, Anthony; Philp, Nancy J.; Pestell, Richard G.; Lisanti, Michael P.

In: Cell Cycle, Vol. 11, No. 7, 01.04.2012, p. 1445-1454.

Research output: Contribution to journalArticle

Sotgia, F, Whitaker-Menezes, D, Martinez-Outschoorn, UE, Flomenberg, N, Birbe, RC, Witkiewicz, AK, Howell, A, Philp, NJ, Pestell, RG & Lisanti, MP 2012, 'Mitochondrial metabolism in cancer metastasis: Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue', Cell Cycle, vol. 11, no. 7, pp. 1445-1454. https://doi.org/10.4161/cc.19841
Sotgia, Federica ; Whitaker-Menezes, Diana ; Martinez-Outschoorn, Ubaldo E. ; Flomenberg, Neal ; Birbe, Ruth C. ; Witkiewicz, Agnieszka K. ; Howell, Anthony ; Philp, Nancy J. ; Pestell, Richard G. ; Lisanti, Michael P. / Mitochondrial metabolism in cancer metastasis : Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue. In: Cell Cycle. 2012 ; Vol. 11, No. 7. pp. 1445-1454.
@article{1d0017a5882b4da89b047fb3ba549db4,
title = "Mitochondrial metabolism in cancer metastasis: Visualizing tumor cell mitochondria and the {"}reverse Warburg effect{"} in positive lymph node tissue",
abstract = "We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the {"}reverse Warburg effect,{"} because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the {"}reverse Warburg effect,{"}our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TO MM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally {"}fuels{"} tumor progression and metastatic dissemination, by {"}feeding{"} mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TO MM20(-) {"}glycolytic{"} cancer cells were rarely observed, indicating that the conventional {"}Warburg effect{"} does not frequently occur in cancer-positive lymph node metastases.",
keywords = "Caveolin-1, Complex IV, Inflammation, MCT4, Metabolic coupling, Metastasis, Mitochondria, Monocarboxylic acid transporter, Oxidative stress, OXPHOS, SLC16A3, TOMM20, Tumor stroma, Two-compartment tumor metabolism",
author = "Federica Sotgia and Diana Whitaker-Menezes and Martinez-Outschoorn, {Ubaldo E.} and Neal Flomenberg and Birbe, {Ruth C.} and Witkiewicz, {Agnieszka K.} and Anthony Howell and Philp, {Nancy J.} and Pestell, {Richard G.} and Lisanti, {Michael P.}",
year = "2012",
month = "4",
day = "1",
doi = "10.4161/cc.19841",
language = "English (US)",
volume = "11",
pages = "1445--1454",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "7",

}

TY - JOUR

T1 - Mitochondrial metabolism in cancer metastasis

T2 - Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue

AU - Sotgia, Federica

AU - Whitaker-Menezes, Diana

AU - Martinez-Outschoorn, Ubaldo E.

AU - Flomenberg, Neal

AU - Birbe, Ruth C.

AU - Witkiewicz, Agnieszka K.

AU - Howell, Anthony

AU - Philp, Nancy J.

AU - Pestell, Richard G.

AU - Lisanti, Michael P.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the "reverse Warburg effect," because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the "reverse Warburg effect,"our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TO MM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally "fuels" tumor progression and metastatic dissemination, by "feeding" mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TO MM20(-) "glycolytic" cancer cells were rarely observed, indicating that the conventional "Warburg effect" does not frequently occur in cancer-positive lymph node metastases.

AB - We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the "reverse Warburg effect," because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the "reverse Warburg effect,"our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TO MM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally "fuels" tumor progression and metastatic dissemination, by "feeding" mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TO MM20(-) "glycolytic" cancer cells were rarely observed, indicating that the conventional "Warburg effect" does not frequently occur in cancer-positive lymph node metastases.

KW - Caveolin-1

KW - Complex IV

KW - Inflammation

KW - MCT4

KW - Metabolic coupling

KW - Metastasis

KW - Mitochondria

KW - Monocarboxylic acid transporter

KW - Oxidative stress

KW - OXPHOS

KW - SLC16A3

KW - TOMM20

KW - Tumor stroma

KW - Two-compartment tumor metabolism

UR - http://www.scopus.com/inward/record.url?scp=84860333164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860333164&partnerID=8YFLogxK

U2 - 10.4161/cc.19841

DO - 10.4161/cc.19841

M3 - Article

VL - 11

SP - 1445

EP - 1454

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 7

ER -