Journal article
The reverse Warburg effect Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts
Cell cycle (Georgetown, Tex.), v 9(10), pp 1960-1971
15 May 2010
PMID: 20495363
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- The reverse Warburg effect Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts
- Creators
- Gloria Bonuccelli - Thomas Jefferson UniversityDiana Whitaker-Menezes - Thomas Jefferson UniversityRemedios Castello-Cros - Thomas Jefferson UniversityStephanos Pavlides - Thomas Jefferson UniversityRichard G. Pestell - Thomas Jefferson UniversityAlessandro Fatatis - Drexel UniversityAgnieszka K. Witkiewicz - Thomas Jefferson UniversityMatthew G. Vander Heiden - MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USAGemma Migneco - Thomas Jefferson UniversityBarbara Chiavarina - Thomas Jefferson UniversityPhilippe G. Frank - Thomas Jefferson UniversityFranco Capozza - Thomas Jefferson UniversityNeal Flomenberg - Thomas Jefferson UniversityUbaldo E. Martinez-Outschoorn - Thomas Jefferson UniversityFederica Sotgia - Thomas Jefferson UniversityMichael P. Lisanti - Thomas Jefferson University
- Publication Details
- Cell cycle (Georgetown, Tex.), v 9(10), pp 1960-1971
- Publisher
- Taylor & Francis
- Number of pages
- 12
- Grant note
- R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660; R01-CA-70896; R01-CA-75503; R01-CA-86072; R01-CA-107382 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) American Cancer Society (ACS); American Cancer Society Susan G. Komen Breast Cancer Foundation Dr. Ralph and Marian C. Falk Medical Research Trust Pennsylvania Department of Health W.W. Smith Charitable Trust P30-CA-56036 / NIH/NCI Cancer Center; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Susan G. Komen Career Catalyst Grant; Susan G. Komen Breast Cancer Foundation Breast Cancer Alliance, Inc. R01CA070896 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Margaret Q. Landenberger Research Foundation R01AR055660 / NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000278015900024
- Scopus ID
- 2-s2.0-77953551959
- Other Identifier
- 991019168073904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology