Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle

The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 01/2012; 11(2):253-63. DOI: 10.4161/cc.11.2.19006
Source: PubMed

ABSTRACT Aging drives large systemic reductions in oxidative mitochondrial function, shifting the entire body metabolically towards aerobic glycolysis, a.k.a, the Warburg effect. Aging is also one of the most significant risk factors for the development of human cancers, including breast tumors. How are these two findings connected? One simplistic idea is that cancer cells rebel against the aging process by increasing their capacity for oxidative mitochondrial metabolism (OXPHOS). Then, local and systemic aerobic glycolysis in the aging host would provide energy-rich mitochondrial fuels (such as L-lactate and ketones) to directly "fuel" tumor cell growth and metastasis. This would establish a type of parasite-host relationship or "two-compartment tumor metabolism", with glycolytic/oxidative metabolic-coupling. The cancer cells ("the seeds") would flourish in this nutrient-rich microenvironment ("the soil"), which has been fertilized by host aging. In this scenario, cancer cells are only trying to save themselves from the consequences of aging, by engineering a metabolic mutiny, through the amplification of mitochondrial metabolism. We discuss the recent findings of Drs. Ron DePinho (MD Anderson) and Craig Thomspson (Sloan-Kettering) that are also consistent with this new hypothesis, linking cancer progression with metabolic aging. Using data mining and bioinformatics approaches, we also provide key evidence of a role for PGC1a/NRF1 signaling in the pathogenesis of (1) two-compartment tumor metabolism, and (2) mitochondrial biogenesis in human breast cancer cells.

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    • "Importantly, changes in mitochondrial respiration also contribute to metabolic remodeling. However, although reduced mitochondrial electron transport function can support tumor cell proliferation, mitochondrial electron transport function is also required for tumor formation [40] and has been shown to be favored by some tumor cells [41] [42] [43] [44] [45]. In particular, although highly aggressive tumors can be highly glycolytic, this is not always associated with reduced oxygen consumption [5]. "
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    ABSTRACT: Tumor formation and spread via the circulatory and lymphatic drainage systems is associated with metabolic reprogramming that often includes increased glycolytic metabolism relative to mitochondrial energy production. However, cells within a tumor are not identical due to genetic change, clonal evolution and layers of epigenetic reprogramming. In addition, cell hierarchy impinges on metabolic status while tumor cell phenotype and metabolic status will be influenced by the local microenvironment including stromal cells, developing blood and lymphatic vessels and innate and adaptive immune cells. Mitochondrial mutations and changes in mitochondrial electron transport contribute to metabolic remodeling in cancer in ways that are poorly understood. This review concerns the role of mitochondria, mitochondrial mutations and mitochondrial electron transport function in tumorigenesis and metastasis. It is concluded that mitochondrial electron transport is required for tumor initiation, growth and metastasis. Nevertheless, defects in mitochondrial electron transport that compromise mitochondrial energy metabolism can contribute to tumor formation and spread. These apparently contradictory phenomena can be reconciled by cells in individual tumors in a particular environment adapting dynamically to optimally balance mitochondrial genome changes and bioenergetic status. Tumors are complex evolving biological systems characterized by genetic and adaptive epigenetic changes. Understanding the complexity of these changes in terms of bioenergetics and metabolic changes will permit the development of better combination anticancer therapies. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
    Biochimica et Biophysica Acta 10/2013; 1840(4). DOI:10.1016/j.bbagen.2013.10.016 · 4.66 Impact Factor
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    • "EMT in cancer progression and organ fibrosis is associated with aging (Mani et al., 2008; Chaturvedi and Hass, 2011; Pannarale et al., 2010). Indeed, aging is one of the single most important risk factors associated with cancer with nearly 65% of cancers occurring in patients R65 years old (Ertel et al., 2012). Similarly, fibrosis is a hallmark of pathogenesis associated with aging in many organs (Abrass et al., 1995). "
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    ABSTRACT: The epithelial-to-mesenchymal transition (EMT) is important for the development of cancer metastases and organ fibrosis, conditions prevalent in aging. Because sirtuins affect the pathology of aging, we tested the effect of SirT1 on EMT. Reduced SIRT1 levels in HMLER breast cancer cells led to increased metastases in nude mice, and the loss of SIRT1 in kidney tubular epithelial cells exacerbated injury-induced kidney fibrosis. SIRT1 reduces EMT in cancer and fibrosis by deacetylating Smad4 and repressing the effect of TGF-β signaling on MMP7, a Smad4 target gene. Consequently, less E-cadherin is cleaved from the cell surface and β-catenin remains bound to E-cadherin at the cell-cell junctions. Our findings suggest that the SIRT1/Smad4/β-catenin axis may be a target for diseases driven by EMT.
    Cell Reports 04/2013; 3(4). DOI:10.1016/j.celrep.2013.03.019 · 8.36 Impact Factor
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    • "The metabolism of tumour cells is characteristically shifted towards cytosolic glycolysis [18,19], as first reported by Otto Warburg [20]. However, respiratory activity is not necessarily compromised [21,22] and has recently been proposed to be central to cancer progression [23]. Consensus has yet to be reached on the reasons for these complex metabolic switches, but the high energy and macromolecular precursor demands of rapidly growing tumours may provide an explanation [24]. "
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    ABSTRACT: The dipeptide carnosine (beta-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age-related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells.
    Chemistry Central Journal 02/2013; 7(1):38. DOI:10.1186/1752-153X-7-38 · 2.19 Impact Factor
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