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Cancer Metabolism New Validated Targets For Essay

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Oncotarget, August, Vol.4, No 8

www.impactjournals.com/oncotarget/

Cancer Metabolism: New Validated Targets for Drug Discovery
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 to: Federica Sotgia, email: [email protected] Correspondence to: Ubaldo E. Martinez-Outschoorn, email: [email protected] Correspondence to: Michael P. Lisanti, email: [email protected] 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

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Metabolic-symbiosis represents a paradigm shift in
cell biology and cancer metabolism [1-20]. In this simple
metabolic model, catabolic fibroblasts fuel the growth of
adjacent anabolic cancer cells, via energy transfer (Figure
1) [2-4, 7, 12, 13, 15, 17, 19-53]. Catabolic stromal cells
produce high-energy mitochondrial “biofuels”, such as
L-lactate, ketone bodies, glutamine, other amino acids,
and free-fatty acids, for cancer cells to use as substrates
for OXPHOS and as biomass. [38, 40].
Catabolic fibroblasts also show a pro-inflammatory
phenotype, due to oxidative stress and NFkB activation,
which leads to cytokine production. This, in turn, attracts
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and serves to activate inflammatory cells (macrophages
and neutrophils), which produce more ROS and hydrogen
peroxide species. These findings link inflammation
directly with energy transfer to anabolic cancer cells [2,
41, 42, 54, 55], explaining how inflammation energetically
promotes tumor initiation and cancer progression.
To stringently test the validity of these energy
transfer mechanism(s), stable cell lines of constitutively
catabolic fibroblasts were generated by genetically
increasing glycolysis, ketogenesis, autophagy, mitophagy,
oxidative stress, and/or senescence. This was accomplished
by the recombinant over-expression or knock-down of key
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Oncotarget 2013; 4: 1309-1316

metabolic target genes in hTERT-immortalized fibroblasts.
Similar results were obtained by the genetic manipulation
of either growth factors or extracellular matrix proteins,
indicating that these “signaling networks” also converge on catabolic metabolism in stromal fibroblasts.
These results are summarized in Table 1, which lists
nearly 30 catabolic fibroblast cell lines that have been
generated, to date [1-20]. Remarkably, these catabolic
fibroblasts [56] effectively promoted tumor growth and/
or metastasis, in pre-clinical animal models (xenografts in
nude mice) [1-20]. Similar results have also been obtained
by using a syngeneic orthotopic animal model, employing
the mammary fat pads of Cav-1 (-/-) null mice, as the
catabolic host microenvironment for tumor growth [57].
Conversely, over-expression of metabolic genes that
drive increased mitochondrial biogenesis or OXPHOS in
epithelial cancer cells, also effectively promoted tumor
growth, and induced autophagy-resistance (Table 1) [4, 8,
18-20].
As metabolic-symbiosis may represent the
underlying basis of drug-resistance [31, 32], and/or
the escape mechanism [35, 43, 44, 47, 48] during antiangiogenic therapy [53], new drugs that target metabolicsymbiosis may prove to be effective in patients with recurrent cancers and even for the treatment of advanced

metastatic disease [25-27, 35, 43].
The existence of metabolic-symbiosis (a.k.a., twocompartment tumor metabolism) has also been directly validated in human breast cancer tissue sections, by
employing mitochondrial activity staining in situ. Using
this approach, it is clear that oxidative, mitochondrialrich cancer cell nests, are physically surrounded by

glycolytic, mitochondrial-poor stromal fibroblasts (Figure
2) [58]. Virtually identical results were also obtained with metabolic protein biomarkers in primary breast tumors and
secondary lymph-node metastases (Figure 3), reflecting a
common organizing principle, with the juxtaposition of
oxidative and glycolytic energetic compartments [52, 59].
As such, tumor architecture also “mirrors” these energybased tumor-stromal interactions. Remarkably, new studies suggest that normal
adjacent epithelial cells, and stromal adipocytes, can also
serve as function...

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