Oncotarget

Research Perspectives:

Cancer Metabolism: New Validated Targets for Drug Discovery

Federica Sotgia, Ubaldo E. Martinez-Outschoorn, Michael P Lisanti _

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Oncotarget. 2013; 4:1309-1316. https://doi.org/10.18632/oncotarget.1182

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Abstract

Federica Sotgia1, Ubaldo E. Martinez-Outschoorn2, and Michael P. Lisanti1

1 Manchester Breast Centre & Breakthrough Breast Cancer Research Unit, Faculty Institute of Cancer Sciences, University of Manchester, UK

2 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA

Correspondence:

Federica Sotgia, email:

Ubaldo E. Martinez-Outschoorn, email:

Michael P. Lisanti, email:

Keywords: cancer metabolism; therapeutic targets; drug discovery; oncogenes; tumor suppressors; oxidative stress; glycolysis; cancer associated fibroblast; tumor microenvironment; metabolic symbiosis; anti-angiogenic therapy

Received: July 15, 2013 Accepted: July 21, 2013 Published: July 22, 2013

Abstract

Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of “metabolic-symbiosis” has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibroblasts harboring ATG16L1 increase tumor cell metastasis by >11.5-fold, despite the fact that genetically identical cancer cells were used. Taken together, these studies provide >40 novel validated targets, for new drug discovery and anti-cancer therapy. Since anabolic cancer cells amplify their capacity for oxidative mitochondrial metabolism, we should consider therapeutically targeting mitochondrial biogenesis and OXPHOS in epithelial cancer cells. As metabolic-symbiosis promotes drug-resistance and may represent the escape mechanism during anti-angiogenic therapy, new drugs targeting metabolic-symbiosis may also be effective in cancer patients with recurrent and advanced metastatic disease.


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