Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1α and HIF2α in tumor-associated fibroblasts and human breast cancer cells.
Authors
Chiavarina, BMartinez-Outschoorn, U
Whitaker-Menezes, D
Howell, Anthony
Tanowitz, Herbert B
Pestell, R
Sotgia, Federica
Lisanti, Michael P
Affiliation
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Stem Cell Biology & Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.Issue Date
2012-09-01
Metadata
Show full item recordAbstract
Hypoxia-inducible factor (HIF) 1α and 2α are transcription factors responsible for the cellular response to hypoxia. The functional roles of HIF1α and HIF2α in cancer are distinct and vary among different tumor types. The aim of this study was to evaluate the compartment-specific role(s) of HIF1α and HIF2α in breast cancer. To this end, immortalized human fibroblasts and MDA-MB-231 breast cancer cells carrying constitutively active HIF1α or HIF2α mutants were analyzed with respect to their metabolic function(s) and ability to promote tumor growth in an in vivo setting. We observed that activation of HIF1α, but not HIF2α, in stromal cells promotes a shift toward aerobic glycolysis, with increased L-lactate production and a loss of mitochondrial activity. In a xenograft model, HIF1α-activated fibroblasts promoted the tumor growth of co-injected MDA-MB-231 cells without an increase in angiogenesis. Conversely, HIF2α-activated stromal cells did not favor tumor growth and behaved as the empty vector controls. Similarly, activation of HIF1α, but not HIF2α, in MDA-MB-231 cells promoted a shift toward aerobic glycolysis, with increased glucose uptake and L-lactate production. In contrast, HIF2α activation in cancer cells increased the expression of EGFR, Ras and cyclin D1, which are known markers of tumor growth and cell cycle progression. In a xenograft model, HIF1α activation in MDA-MB-231 cells acted as a tumor suppressor, resulting in an almost 2-fold reduction in tumor mass and volume. Interestingly, HIF2α activation in MDA-MB-231 cells induced a significant ~2-fold-increase in tumor mass and volume. Analysis of mitochondrial activity in these tumor xenografts using COX (cytochrome C oxidase) staining demonstrated elevated mitochondrial oxidative metabolism (OXPHOS) in HIF2α-tumors. We conclude that the role(s) of HIF1α and HIF2α in tumorigenesis are compartment-specific. HIF1α acts as a tumor promoter in stromal cells but as a tumor suppressor in cancer cells. Conversely, HIF2α is a tumor promoter in cancer cells. Mechanistically, HIF1α-driven aerobic glycolysis in stromal cells supports cancer cell growth via the paracrine production of nutrients (such as L-lactate) that can "feed" cancer cells. However, HIF1α-driven aerobic glycolysis in cancer cells inhibits tumor growth. Finally, HIF2α activation in cancer cells induces the expression of known pro-oncogenic molecules and promotes the mitochondrial activity of cancer cells.Citation
Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1α and HIF2α in tumor-associated fibroblasts and human breast cancer cells. 2012, 11 (17):3280-9 Cell CycleJournal
Cell CycleDOI
10.4161/cc.21643PubMed ID
22894905Type
ArticleLanguage
enISSN
1551-4005ae974a485f413a2113503eed53cd6c53
10.4161/cc.21643
Scopus Count
Collections
Related articles
- HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis.
- Authors: Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP
- Issue date: 2010 Sep 1
- Compartment-specific activation of PPARγ governs breast cancer tumor growth, via metabolic reprogramming and symbiosis.
- Authors: Avena P, Anselmo W, Whitaker-Menezes D, Wang C, Pestell RG, Lamb RS, Hulit J, Casaburi I, Andò S, Martinez-Outschoorn UE, Lisanti MP, Sotgia F
- Issue date: 2013 May 1
- Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: connecting TGF-β signaling with "Warburg-like" cancer metabolism and L-lactate production.
- Authors: Guido C, Whitaker-Menezes D, Capparelli C, Balliet R, Lin Z, Pestell RG, Howell A, Aquila S, Andò S, Martinez-Outschoorn U, Sotgia F, Lisanti MP
- Issue date: 2012 Aug 15
- CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth.
- Authors: Capparelli C, Whitaker-Menezes D, Guido C, Balliet R, Pestell TG, Howell A, Sneddon S, Pestell RG, Martinez-Outschoorn U, Lisanti MP, Sotgia F
- Issue date: 2012 Jun 15
- Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection.
- Authors: Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, Chiavarina B, Pestell RG, Howell A, Sotgia F, Lisanti MP
- Issue date: 2011 Dec 1